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J Appl Physiol 95: 1493-1498, 2003. First published June 27, 2003; doi:10.1152/japplphysiol.00344.2002
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Autonomic and vascular responses to reduced limb perfusion

Joseph C. Daley, III,1 Mazhar H. Khan,2 Cynthia S. Hogeman,2 and Lawrence I. Sinoway2,3

Divisions of 1Pulmonary, Allergy, and Critical Care and 2Cardiology, The Pennsylvania State University College of Medicine, The Milton S. Hershey Medical Center, Hershey 17033; and 3Lebanon Veterans Affairs Medical Center, Lebanon, Pennsylvania 17042

Submitted 17 April 2002 ; accepted in final form 23 June 2003


   ABSTRACT
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METHODS
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 DISCUSSION
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The purpose of this study was to examine hemodynamic responses to graded muscle reflex engagement in human subjects. We studied seven healthy human volunteers [24 ± 2 (SE) yr old; 4 men, 3 women] performing rhythmic handgrip exercise [40% maximal voluntary contraction (MVC)] during ambient and positive pressure exercise (+10 to +50 mmHg in 10-mmHg increments every minute). Muscle sympathetic nerve activity (MSNA), mean arterial blood pressure (MAP), and mean blood velocity were recorded. Plasma lactate, hydrogen ion concentration, and oxyhemoglobin saturation were measured from venous blood. Ischemic exercise resulted in a greater rise in both MSNA and MAP vs. nonischemic exercise. These heightened autonomic responses were noted at +40 and +50 mmHg. Each level of positive pressure was associated with an immediate fall in flow velocity and forearm perfusion pressure. However, during each minute, perfusion pressure increased progressively. For positive pressure of +10 to +40 mmHg, this was associated with restoration of flow velocity. However, at +50 mmHg, flow was not restored. This inability to restore flow was seen at a time when the muscle reflex was clearly engaged (increased MSNA). We believe that these findings are consistent with the hypothesis that before the muscle reflex is clearly engaged, flow to muscle is enhanced by a process that raises perfusion pressure. Once the muscle reflex is clearly engaged and MSNA is augmented, flow to muscle is no longer restored by a similar rise in perfusion pressure, suggesting that active vasoconstriction within muscle is occurring at +50 mmHg.

muscle blood flow; sympathetic nervous system; ischemia

DURING EXERCISE THE SYMPATHETIC nervous system is activated. This activation results in increased heart rate (HR), mean arterial blood pressure (MAP) and peripheral vasoconstriction (2, 13-15, 19-21, 26, 30). Two neural systems may contribute to this process: central command and the muscle reflex. Central command is a feedforward central neural process in which a motoneuron recruitment is thought to parallel sympathetic nervous system engagement (9). Activation of the muscle reflex results from stimulation of metabolite and mechanically sensitive afferents within contracting skeletal muscle (2, 18). Whether engagement of these systems acts to increase or decrease flow to exercising muscle is unclear. This issue is complicated because reflex increases in blood pressure would tend to raise muscle flow and reflex vasoconstriction within exercising muscle would act to reduce flow delivery.

In this study, the effects of graded muscle ischemia on sympathetic responses were examined. We measured HR, MAP, muscle sympathetic nerve activity (MSNA), limb metabolites, and limb flow velocity. The results of these studies suggest that flow limitation evokes a reflex increase in perfusion pressure that restores blood flow to exercising muscle. At high levels of ischemia, this increase in perfusion pressure is no longer flow restorative. We speculate that this is due to vasoconstriction within the exercising ischemic limb.


   METHODS
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Subjects. Seven healthy volunteers [24 ± 2 (SE) yr old; 4 men, 3 women] participated in the study. The subjects were normotensive, nonsmokers, nonobese, and not taking any medications. Each subject gave written, informed consent, and all procedures used in the study had prior approval of the Institutional Review Board of The Milton S. Hershey Medical Center (MSHMC) of the Pennsylvania State University. Each subject performed two exercise protocols on each arm.

Blood flow. Brachial artery mean blood velocity (MBV) was measured continuously and collected on-line at 100 Hz with a 4-MHz continuous-wave Doppler probe (model 500M, Multigon Industries, Yonkers, NY). Doppler signal strength was optimized by using both visual and auditory feedback of shift frequencies.

Brachial artery diameter. Brachial artery diameter was measured continuously in four subjects with a pulsed-wave Doppler probe (range of 5-12 MHz; System 5000, Advanced Technology Laboratories, Bothell, WA). To obtain time course analysis of MBV and MAP, three- to five-beat averages of blood velocity were obtained at baseline and at 10-s intervals during exercise.

Exercise paradigm. Subjects reported to the Hershey Medical Center General Clinical Research Center (GCRC) and received a prestudy history and physical examination. The protocols consisted of a 5-min baseline period, followed by 6 min of exercise and 5 min of recovery (Fig. 1). Maximal voluntary contraction (MVC) was assessed in each arm separately. In protocol 1, the ambient pressure trial, subjects performed rhythmic handgrip exercise at ~40% MVC (30 1-s contractions/min). Protocol 1 was designed to determine the responses during nonischemic, free-flow conditions. Protocol 2, the positive pressure trial, was a variant of the ischemic exercise protocol described by Joyner et al. (7, 8) and was previously used in our laboratory (17). This protocol was designed to evaluate reflex increases in MAP and MSNA in response to graded reductions in muscle perfusion pressure. The ambient pressure trial and positive pressure trial are illustrated schematically in Fig. 1. Venous blood samples were obtained during baseline, at the end of each minute of exercise, and during recovery. To eliminate arm dominance as a confounding variable, all subjects performed both protocols with each arm and the study sequence was randomized. The arm tank was a specially constructed, sealed wooden tank with an air pressure regulator and continuous pressure transducer attached. For the positive pressure trial, the tank pressure was adjusted in increments of 10 mmHg/min until +50 mmHg above ambient barometric pressure was achieved. Thirty minutes of rest separated each exercise trial. During each level of positive pressure, the perfusion pressure and flow velocity were also examined every 10 s. At each level of positive pressure, the initial values for perfusion pressure and velocity were subtracted from the last two to determine time course of perfusion pressure and flow velocity adjustments.



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  		Fig. 1. Schematic diagram of exercise protocol. E1-E6, minutes 1-6 of rhythmic handgrip exercise. Arrows, venous blood sampling.

 

HR and blood pressure. HR was monitored via three-lead electrocardiography. Systemic blood pressure (BP) was measured continuously by using photoplethysmography (Finapres, Ohmeda, Madison, WI) on the nonexercising hand. Resting BP was obtained with an automated sphygmomanometer (Dinamap, Critikon, Tampa, FL). Perfusion pressure was calculated by subtracting external arm tank pressure from MAP (29).

Microneurography. The microneurographic technique provides direct recordings of sympathetic nerve traffic directed to blood vessels in skeletal muscle. The method, as used in our laboratory, has been described previously (3, 24, 27).

Briefly, multiunit recordings of postganglionic MSNA were obtained from the peroneal nerve with an insulated 200-µm-diameter tungsten electrode tapered to an uninsulated 1- to 5-µm tip. The microelectrode was inserted percutaneously into the peroneal nerve posterior to the head of the fibula, with a reference electrode inserted subcutaneously 1-3 cm from the active electrode. The nerve activity was amplified, band-pass filtered (700-2,000 Hz), rectified, and then integrated to obtain a mean voltage neurogram. We counted the number of bursts and expressed the data in this report as bursts per minute.

Blood samples. Venous blood was obtained via a 20-gauge intravenous catheter placed in a retrograde fashion in the deep antecubital vein of the exercising forearm. Plasma was obtained immediately by centrifuge of the specimen for 30 s at 3,000 rpm (model 5415C, Eppendorf, Hamburg, Germany). Analysis of the samples for metabolites was conducted with Radiometer model ABL 510 and EML 610 analyzers (Copenhagen NV, Denmark) in the Core Laboratory of the MSHMC GCRC. Arterial oxyhemoglobin saturation was assumed to be 95% for the purpose of calculations. Oxygen extraction was estimated by the difference between arterial and venous oxyhemoglobin saturation. Oxygen uptake was calculated in the usual fashion, using MBV as a surrogate for flow in the equation mO2 = x (SaO2 - SvO2)·hemoglobin (in g/dl)·1.34 ml/g (oxygen-carrying capacity of hemoglobin) (mO2 = flow, SaO2 = arterial oxyhemoglobin saturation, SvO2 = venous oxyhemoglobin saturation). This method has been employed previously (23).

Statistics. Each of the seven subjects performed the exercise paradigm under two conditions: ambient pressure and positive pressure. These protocols were repeated twice on each subject (left and right arm) to eliminate arm dominance as a confounding variable. Repeated-measures ANOVA models were fit to metabolic and hemodynamic responses to assess changes from baseline at different exercise paradigm points between ambient pressure and positive pressure. A Bonferroni adjustment was made to all simple effects comparison P values between ambient pressure and positive pressure to account for multiple testing. For all analyses, P < 0.05 was considered significant. Data are reported as means ± SE. Portions of the subjects' data have been reported elsewhere in a study that examined the effects of aging on the muscle reflex (11).


   RESULTS
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In four of the seven subjects, brachial artery diameter was measured (Table 1). No paradigm or between-group effects on arterial diameter were noted. Given that mean blood flow (MBF) can be expressed as MBF = MBV·{pi}·(brachial artery diameter/2)2 and that arterial diameter (or radius) did not change with forearm pressure, we used MBV as a surrogate for MBF.


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  		Table 1. Forearm response to ambient pressure and positive pressure exercise

 

The data are presented in Table 1 and Figs. 2, 3, 4, 5, 6, 7. Ischemic exercise raised the perceived level of effort (Fig. 2). Rhythmic handgrip exercise during incremental external positive tank pressure resulted in higher plasma lactate (P < 0.02) and higher hydrogen ion concentrations at +40 and +50 mmHg (Fig. 3).



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  		Fig. 2. Borg data for perceived level of effort obtained during the 2 paradigms. Values are means ± SE. NS, not significant. *P < 0.05 (by Dunnett's test).

 


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  		Fig. 3. {Delta} Hydrogen ion concentration (A; {Delta}H+)and {Delta} plasma lactate (B; {Delta}lactate) during ambient and positive pressure conditions. {Delta} Data represent the change from baseline. Values are means ± SE. *P < 0.05 (by Dunnett's test). Level of positive pressure of E2-E6 as in Fig. 1.

 


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  		Fig. 4. {Delta} Muscle sympathetic nerve activity ({Delta}Bursts; A), {Delta} mean arterial blood pressure ({Delta}MAP; B), mean blood velocity ({Delta}MBV; C), and {Delta} conductance (D) in ambient and positive pressure conditions. {Delta} Data represent the change from baseline. Values are means ± SE. Conductance = flow velocity ÷ (MAP - tank pressure) and is expressed in arbitrary units. *P < 0.05 (by Dunnett's test). Level of positive pressure at E2-E6 as in Fig. 1.

 


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  		Fig. 5. {Delta} Oxygen extraction ({Delta}O2 extraction; A) and {Delta}muscle oxygen uptake ({Delta}mO2; B) in ambient and positive pressure conditions. {Delta} Data represent change from baseline. Values are means ± SE. au, Arbitrary units. *P < 0.05 (by Dunnett's test). Level of positive pressure at E2-E6 as in Fig. 1.

 


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  		Fig. 6. Time course of MBV and perfusion pressure during ambient (A) and positive pressure (B) exercise. Perfusion pressure = MAP - forearm tank pressure. Small intervals on the x-axis represent 10 s of time. B, baseline. Values are means ± SE. Dashed vertical lines represent changes from one level of positive pressure to the next. MBV is in cm/s; perfusion pressure is in mmHg.

 


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  		Fig. 7. Plot of changes in flow velocity vs. perfusion pressure at each level of positive pressure. Values are means ± SE.

 

Hemodynamic responses. In the ambient pressure trial, MSNA, MAP, MBV, and the ratio of MBV to perfusion pressure rose gradually as a function of exercise duration. Of note, application of incremental external positive pressure resulted in a greater rate of rise of MAP, reduced MBV and increased MSNA vs. ambient pressure (Fig. 4). Compared with freely perfused handgrip, positive pressure augmented the MAP and MSNA response at +40 mmHg and +50 mmHg (Fig. 4). Despite the effects of positive pressure on flow velocity, oxygen consumption was maintained (Fig. 5).

Ten-second analyses of MBV and perfusion pressure during the ischemic paradigm are shown in Fig. 6. Positive forearm pressure led to a prompt reduction in flow at each workload. At each level of positive pressure except the last, flow was restored by the rise in perfusion pressure (Fig. 7).


   DISCUSSION
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 ABSTRACT
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Application of external positive pressure to the forearm reduced perfusion to the exercising muscle compared with perfusion during the ambient pressure condition. This led to greater plasma lactate concentration and increased hydrogen ion concentration (at +40 and +50 mmHg; Fig. 3). Progressive ischemia led to greater MAP and MSNA responses (Fig. 4) than were seen during freely perfused handgrip. Of note, MAP and MSNA were greater during +40 and +50 mmHg. Analysis of flow velocity and perfusion pressure at each level of positive pressure demonstrated that the initial fall in flow velocity was restored by the rise in perfusion pressure at all levels of positive pressure except the last (Figs. 6 and 7). Thus, at the greatest level of positive pressure (+50 mmHg) where MSNA was clearly augmented, perfusion pressure similar to that seen at +10 to +40 mmHg did not restore flow to exercising muscle. These findings raise two key questions: 1) what is the mechanism for flow restoration at the lower levels of positive pressure? and 2) why does flow not rise with the increase in perfusion pressure seen at +50 mmHg?

With regard to the first question, it is unlikely that this effect is due to engagement of the metaboreflex at +10 to +30 mmHg. There was little increase in hydrogen ion or lactate concentration, and MSNA was augmented only at +40 mmHg. On the basis of prior literature, if the metaboreflex were engaged at the lower levels of positive pressure, we would have anticipated a rise in MSNA and/or some increase in markers of muscle ischemia (5, 28).

Could the increased perfusion pressure have been due to stimulation of the muscle mechanoreflex? This is clearly possible, because it has shown that mechanoreflex mediated autonomic responses are seen early in exercise and can be enhanced by ischemia (1, 16). However, if mechanoreceptor engagement were responsible for the restoration of flow at the lower workloads, we would have expected a rise in MSNA before the +40-mmHg level of positive pressure (12).

Is it possible that muscle ischemia enhances central command? Ischemic exercise is clearly perceived as more fatiguing than nonischemic work (Fig. 2), and it has been suggested that central command is linked to {alpha}-motoneuron activity and the perceived level of effort. It is known that muscle afferent feedback facilitates motoneuron activity (10) and that postexercise ischemia prevents motoneuron firing rate from returning to baseline values (4). Moreover, human studies suggest that central command evokes increases in HR and BP and far less impressive increases in MSNA (31, 32). In fact, it has been suggested that central command can act to decrease peripheral sympathetic constrictor outflow (25) and to evoke an increase in flow to skeletal muscle (33). Thus we postulate that ischemia augments {alpha}-motoneurons and autonomic responses in a parallel fashion through a mechanism that involves central locomotor regions of the brain. We further speculate that these systems act to raise muscle perfusion to exercising muscle.

With regard to the second question, we believe that flow was not restored at +50 mmHg because the muscle reflex was engaged and thus sympathetic constriction was present within the exercising muscle. This hypothesis is based on the fact that at +50 mmHg, MSNA was clearly augmented. An increase in MSNA in the absence of a fall in BP should be associated with limb vasoconstriction in nonexercising muscle (22). We acknowledge that we have no data to demonstrate that MSNA and more importantly norepinephrine at the neurovascular junction is the same in exercising and nonexercising muscle. However, on the basis of the limited data currently present, we suspect that MSNA is likely to be similar in exercising and nonexercising muscle (6).

In conclusion, external positive pressure leads to flow reduction to muscle. At +10 to +40 mmHg, external pressure a rise in perfusion pressure acts to restore flow to muscle. At +50 mmHg, flow was no longer restored by the rise in perfusion pressure. We postulate that at +10 to +40 mmHg, autonomic adjustments do not include vasoconstriction within the active muscle. At +50 mmHg, we postulate that autonomic adjustments include an increase in sympathetic drive to muscle.


   DISCLOSURES
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 DISCLOSURES
ACKNOWLEDGMENTS
 REFERENCES
 
This work was supported by a Veterans Administration Merit Review Award (to L. I. Sinoway); National Institutes of Health (NIH) Grants R01 AG-12227 (to L. I. Sinoway), R01 HL-60800 (to L. I. Sinoway), K24 HL-04011 (to L. I. Sinoway), K23 RR-16053 (to J. C. Daley), and K30 HL-04092; and NIH-sponsored General Clinical Research Center with National Center for Research Resources Grant M01 RR-10732.


   ACKNOWLEDGMENTS
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REFERENCES
 
The authors greatly appreciate the technical support of Kristen Gray, Tania Mohammed, and Nikki DiVittore, the statistical support of Allen Kunselman, and the superb secretarial support of Jennifer Stoner in preparation of this manuscript.


   FOOTNOTES
 

Address for reprint requests and other correspondence: L. I. Sinoway, Div. of Cardiology, MC H047, The Pennsylvania State University College of Medicine, The Milton S. Hershey Medical Center, P.O. Box 850, Hershey, PA 17033 (E-mail: lsinoway{at}psu.edu).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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 REFERENCES
 

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