We measured brachial and femoral artery flow velocity in eight subjects and peroneal and median muscle sympathetic nerve activity (MSNA) in five subjects during tilt testing to 40°. Tilt caused similar increases in MSNA in the peroneal and median nerves. Tilt caused a fall in femoral artery flow velocity, whereas no changes in flow velocity were seen in the brachial artery. Moreover, with tilt, the increase in the vascular resistance employed (blood pressure/flow velocity) was greater and more sustained in the leg than in the arm. The ratio of the percent increase in vascular resistance in leg to arm was 2.5:1. We suggest that the greater vascular resistance effects in the leg were due to an interaction between sympathetic nerve activity and the myogenic response.
- sympathetic nervous system
- blood pressure regulation
during postural stress, peripheral vasoconstriction occurs. This process appears particularly important in skeletal muscle, where sympathetic vasoconstrictor activity has been demonstrated (16). A second local response evoked by increments in transmural pressure can also cause skeletal muscle vasoconstriction (10). This response, termed the myogenic response, has received relatively less attention than the concept of sympathetic constriction. Consequently, its importance in regulating blood flow in humans is less well established.
The role of the myogenic response has been studied primarily in animals. Lash and Shoukas (11) examined the response of vessel diameter in the spinotrapezius muscle of adult rats to common carotid occlusion with (normal) and without (isobaric) arterial pressure elevation. They demonstrated that during normal occlusion vessel diameter decreased, whereas it was either unchanged or increased during isobaric occlusion. This suggested that a significant portion of the observed arteriolar constriction seen during normal, common carotid occlusion was myogenic in origin. Norepinephrine (NE) has been shown to facilitate vascular responses to changes in transmural pressure. This suggests that an interaction between the sympathetic nervous system and the myogenic response may be present (2).
Baroreflex disengagement occurs when humans stand, leading to an increase in sympathetic vasoconstrictor tone, which is thought to be similar in the arm and the leg (1). Additionally, upright posture increases the transmural pressure in the lower extremities, which should increase myogenic constriction in the dependent limbs. Therefore, if vascular resistance responses in the arm and the leg are similar during head-up tilt (HUT), it could be argued that myogenic influences contribute little to limb blood flow regulation in humans. However, because flow reductions are greater in the leg than in the arm during HUT despite similar changes in muscle sympathetic nerve activity (MSNA), it could be concluded that the myogenic response may be contributing to lower limb flow regulation and blood pressure control.
Hence, this study was undertaken to examine sympathetic and blood flow responses in the upper and lower limbs during tilt in healthy human subjects. Simultaneous recordings of arm and leg MSNA (n = 5) and of brachial and femoral artery mean blood flow velocity (MBV, n = 8) were obtained in the supine and HUT positions. During HUT, the leg was dependent, and the arm was kept at heart level. Our data support the hypothesis that the magnitude of the vasoconstrictor response is enhanced by postural engagement of the myogenic response.
We studied 10 healthy subjects between the ages of 20 and 46 yr (five males and five females). Doppler data in the supine position and in the HUT position were successfully gathered in eight subjects, and complete MSNA data sets (baseline and HUT median and peroneal nerves) were obtained in five subjects. Simultaneous, complete Doppler and MSNA recordings for the entire paradigm were obtained in three subjects. Subject characteristics and studies performed are shown in Table1. All patients underwent a history and physical exam and signed an Institutional Review Board-approved consent form before being studied.
In addition to blood flow velocity measurements (n = 8), mean arterial pressure (MAP; n = 8), heart rate (HR; n = 8), and MSNA (n = 5) were continuously measured. After 5 min of baseline data were collected, the subjects were tilted to 40° (2°/s). Ten minutes of tilt data were then collected. During tilt, considerable efforts were taken to keep the forearm and leg positions stable relative to the position of the electrodes and Doppler probes.
To determine pressure changes over brief periods, we used the Finapres device (Ohmeda; Madison, WI). Care was taken to fit the finger with an appropriate cuff and to stabilize the hand at the level of the heart. Finapres pressures were compared with measurements determined with an automated sphygmomanometer (Dinamap, Critikon; Tampa, FL) at the beginning and end of each study. HR was derived from the electrocardiogram or from the arterial pressure tracing obtained from the Finapres.
MSNA was measured in the median (arm) and peroneal (leg) nerves using the microneurographic technique as previously described in detail (1, 5, 14, 16, 19, 21). With the use of a Grass Stimulator (Quincy, MA), the course of the nerve was externally mapped with a pen-shaped electrode (10–100 V, 0.2 ms, 1 pulse/s). Tungsten recording electrodes were then placed percutaneously in the peroneal and median nerves, and reference electrodes were placed a short distance away from the recording electrodes. The resultant neurograms represented multiunit postganglionic recordings of MSNA (19).
−1 · cm−1).
In addition to baseline data, we analyzed data during the third (T3), fifth (T5), and tenth (T10) minute of HUT at 40°. No data were analyzed during minutes 1 and 2 of tilt because of concerns regarding artifact reductions in limb blood flow due to the change in the subject's position (supine to 40°) relative to the Doppler probe during the early stages of tilt.
Two-way repeated measures analysis of variance were used to examine MSNA. Two within-subject variables were used in the analysis: the tilting paradigm and whether the parameter was measured in the arm or the leg. Flow velocity (brachial and femoral artery), the respective vascular resistance responses, HR, and blood pressure were analyzed using repeated measures one-way analysis of variance. Comparisons to baseline were made using the Dunnett test. A P < 0.05 was considered statistically significant. All values are expressed as means ± SE.
Resting values for HR and MAP are presented in Table 1. The specific subjects in whom complete MSNA and Doppler data sets were obtained are also shown.
HR increased during the tilt procedure (in beats/min: 67 ± 2 baseline, 78 ± 3 T3, 79 ± 3 T5, and 81 ± 2 T10;P < 0.001). MAP increased early in tilt (in mmHg: 102 ± 5 baseline, 107 ± 5 T3, 105 ± 5 T5, and 100 ± 5 T10; P < 0.005).
HUT resulted in a marked increase in MSNA burst frequency (Fig.1) in both the median and peroneal nerves (tilt effect <0.001) with the magnitude of change in the two limbs being similar for all time points (limb main effect P< 0.807; interaction <0.966). Approximately 60% of the individual bursts and all salvos of three or more bursts could be identified in both neurograms at baseline. Approximately 20% of bursts were seen only in the arm and 20% only in the leg. The number of bursts present in both the upper and lower extremities increased with tilt (76% in common with tilt). Figure 2 represents simultaneous neurograms from the median and peroneal nerves during tilt.
Tilt led to a reduction in flow velocity in the leg but not in the arm (Fig. 3). The reduction in flow velocity in the leg was seen during T3 and T5. Vascular resistance in the arm and the leg were affected by the tilt maneuver (tilt main effect: armP < 0.035, leg P < 0.007). In the arm, pointwise comparisons did not demonstrate that resistance at T3, T5, or T10 were higher than baseline, although there was a trend for resistance at T3 to be higher than at baseline (P = 0.06). In the leg, T3 and T5 vascular resistances were both greater than baseline (Fig. 4). When the effects of tilt on vascular resistance were compared in the arm and the leg, we observed that the ratio of the percent increase in vascular resistance was 2.5 times greater in the leg than in the arm.
Data from the three subjects in whom we were able to obtain simultaneous MSNA and Doppler were analyzed separately. Responses were similar to the rest of the group.
In this study, we measured MSNA (median and peroneal nerve,n = 5), MBV (brachial and femoral arteries), MAP, and HR (n = 8) during supine and HUT to 40°. From these data, we derived an index of brachial and femoral artery vascular resistance. The principle findings of this report are that despite comparable increases in arm and leg MSNA during tilt, limb flow velocity fell in the leg but not in the arm, and the vascular resistance responses were greater in the leg than in the arm. In the following section, we will discuss our rationale for performing these experiments. We will review the results obtained and their potential implications.
In agreement with Wallin et al. (21) and Rea and Wallin (14), baseline MSNA and responses to upright tilt were similar in the arm and the leg. It should be noted that similar MSNA responses in the arm and the leg are not seen in response to all interventions. For example, Wallin et al. (21) had subjects perform static handgrip followed by posthandgrip circulatory arrest while MSNA was simultaneously determined in the radial (appropriate forearm) and peroneal nerve. These authors found that the increase in MSNA was greater in the radial than in the peroneal nerve during posthandgrip circulatory arrest. It is possible that sympathetic responses were greater in the forearm than in the leg because of the engagement of a forearm axon reflex in the nonexercising forearm.
Despite similar MSNA responses in the arm and the leg, increases in vascular resistance to tilt were far greater in the leg than in the arm. What are the potential explanations for this finding? We believe the most likely explanation for the greater vasoconstrictor effect in the leg than in the arm during tilt was that the increase in lower limb transmural pressure evoked a myogenic response in blood vessels to skeletal muscle, which was accentuated by sympathoexcitation (11-13). Furthermore, we would speculate that the more moderate vasoconstrictive response observed in the forearm likely represents the effects of sympathoexcitation in the absence of the simultaneous engagement of the myogenic response. We believe this explanation is consistent with prior literature (9, 11-13,17).
However, before accepting this supposition at face value, several alternate explanations for our findings should be considered. First, it is possible that the MSNA response in the arm was composed of both dilator and constrictor fibers, whereas the MSNA response in the leg predominantly reflected activation of vasoconstrictor fibers. Although dilator fibers have been described in animal studies (7,8), recording experiments of the human nerve have not provided strong support for their presence during maneuvers that evoke sympathoexcitation (15). In general, forearm vasodilation is usually associated with a fall in MSNA (1, 20). Additionally, in the present report, the percentage of MSNA discharges seen only in the forearm (not seen in the peroneal nerve recording) fell with tilt. If forearm dilator fibers were playing an important role, we would have expected the percentage of discharges, seen only in the median nerve neurograms, to have increased with tilt.
Second, it is possible that local events within the lower limb skeletal muscle interstitium (surrounding the neurovascular junction) led to an increased rate of release of NE for a given increase in MSNA. Jacob et al. (4) examined arm and leg NE spillover during sodium nitroprusside infusions. In this prior report (4), nitroprusside led to similar increases in spillover in the arms and the legs. On the basis of their report (4), we believe it is unlikely that the rate of release of NE for a given increase in sympathetic discharge was greater in the legs than in the arms in our study.
It is also possible that α-adrenergic receptor sensitivity (or density) is greater in the leg than in the arm (3). Under these circumstances, vasoconstrictor responses would also be greater for a given level of baroreceptor engagement. The results of prior reports are consistent with this possibility. For example, Jacobsen et al. (6), using Xenon clearance, found a statistical trend toward greater increase in lower limb skeletal muscle vascular resistance in the legs than in the arm. A subsequent report by Jacobsen et al. (5), using a strain gauge, demonstrated that lower body negative pressure (LBNP) −15 mmHg led to an increase in vascular resistance ∼50% greater in the leg than the arm (ratio of percent increase in vascular resistance of leg to arm was 1.5:1). LBNP −15 mmHg increases transmural pressure by 15 mmHg, and we previously showed that an increase in transmural pressure of 15 mmHg does not evoke myogenic vasoconstriction in human subjects (18). In the present report, where sympathetic engagement was coupled with a larger increase in transmural pressure, we found that the percent increase in vascular resistance was ∼150% greater in the leg than in the arm (leg-to-arm ratio of 2.5:1). Therefore, we would suggest that two-thirds of the greater vasoconstrictor effect seen in the leg compared with the arm is explained by the limb-related differences in myogenic tone. We further hypothesize that the remaining one-third of the limb-related differences seen with tilt may be due to leg versus arm differences in adrenergic receptor sensitivity.
Finally, it is possible that differences in β-receptor activity in the arms and legs during tilt could explain our results. In other words, it is possible that there are more β-receptors in the upper than in the lower extremities. Therefore, for a given increase in MSNA, more dilation would be seen in the arm than in the leg. Jacob et al. (4) examined regional vascular responses in humans. Interestingly, they found a dissociation between sympathetic activation and vascular responses in the legs compared with the arms. Specifically, they found a relatively lower sensitivity of α1-adrenergic receptor-mediated constriction in the legs as opposed to the arms. Additionally, they found a decreased efficacy of β2-adrenergic-mediated vasodilation in the legs compared with the arms. However, Jacobsen et al. (5) compared arm and leg blood flow responses when β-blockade was coupled with LBNP. They did not observe limb-related differences in the effect of β-blockade flow. On the basis of these conflicting results, definitive conclusions regarding this mechanism cannot be drawn.
Finally, the possibility that the tilt evoked a “local” axon reflex in the leg cannot be excluded. However, based on the known importance of myogenic regulation in animal work, it is believed that engagement of this pressure-sensitive reflex is the most likely explanation for our findings.
In conclusion, there were greater increases in vascular resistance in the femoral artery compared with the brachial artery during HUT, despite similar increases in MSNA in the median and peroneal nerves. This response may be due to the combined effects of sympathoexcitation and engagement of the myogenic response in the lower extremities.
The authors greatly appreciate the technical support of Kristen Gray and Noelle Dahl, the statistical support of Allen Kunselman, and the secretarial support of Jennie Stoner in preparing the manuscript.
This project was supported by National Aeronautics and Space Administration Grants NAG9–1044 (to L. I. Sinoway) and NAG9–1034 (to C. A. Ray), a Veterans Administration Merit Review Award (to L. I. Sinoway), National Heart, Lung, and Blood Institute Grant R01 HL-58503 (to C. A. Ray), and a National Institutes of Health-sponsored General Clinical Research Center with the National Center for Research Resources Grant M01 RR-10732. L. I. Sinoway is a recipient of a National Heart, Lung, and Blood Institute Grant K24 HL-04011 Midcareer Investigator Award in Patient-Oriented Research. V. A. Imadojemu is a recipient of a National Heart, Lung, and Blood Institute Mentored Patient Oriented Research Award Grant K23 HL-04190.
Address for reprint requests and other correspondence: V. A. Imadojemu, Divisions of Cardiology and Pulmonary Allergy and Critical Care, Mail Code H047, The Milton S. Hershey Medical Center, The Pennsylvania State University College of Medicine, P.O. Box 850, Hershey, PA 17033 (E-mail:).
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- Copyright © 2001 the American Physiological Society