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Am J Physiol Heart Circ Physiol 293: H2289-H2295, 2007. First published August 3, 2007; doi:10.1152/ajpheart.01422.2006
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Metabolic forearm vasodilation is enhanced following Bier block with phentolamine

Raman Moradkhan,1 Patrick McQuillan,2 Cynthia Hogeman,1 Andrea Leuenberger,1 Latoya Linton-Frazier,1 and Urs A. Leuenberger1

1Heart & Vascular Institute, and 2Department of Anesthesia, Penn State College of Medicine, Hershey, Pennsylvania

Submitted 28 December 2006 ; accepted in final form 3 August 2007


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
The extent to which sympathetic nerve activity restrains metabolic vasodilation in skeletal muscle remains unclear. We determined forearm blood flow (FBF; ultrasound/Doppler) and vascular conductance (FVC) responses to 10 min of ischemia [reactive hyperemic blood flow (RHBF)] and 10 min of systemic hypoxia (inspired O2 fraction = 0.1) before and after regional sympathetic blockade with the {alpha}-receptor antagonist phentolamine via Bier block in healthy humans. In a control group, we performed sham Bier block with saline. Consistent with {alpha}- receptor inhibition, post-phentolamine, basal FVC (FBF/mean arterial pressure) increased (pre vs. post: 0.42 ± 0.05 vs. 1.03 ± 0.21 units; P < 0.01; n = 12) but did not change in the saline controls (pre vs. post: 0.56 ± 0.14 vs. 0.53 ± 0.08 units; P = not significant; n = 5). Post-phentolamine, total RHBF (over 3 min) increased substantially (pre vs. post: 628 ± 75 vs. 826 ± 92 ml/min; P < 0.01) but did not change in the controls (pre vs. post: 618 ± 66 vs. 661 ± 35 ml/min; P = not significant). In all conditions, compared with peak RHBF, peak skin reactive hyperemia was markedly delayed. Furthermore, post-phentolamine (pre vs. post: 0.43 ± 0.06 vs. 1.16 ± 0.17 units; P < 0.01; n = 8) but not post-saline (pre vs. post: 0.93 ± 0.16 vs. 0.87 ± 0.19 ml/min; P = not significant; n = 5), the FVC response to hypoxia (arterial O2 saturation = 77 ± 1%) was markedly enhanced. These data suggest that sympathetic vasoconstrictor nerve activity markedly restrains skeletal muscle vasodilation induced by local (forearm ischemia) and systemic (hypoxia) vasodilator stimuli.

vasodilation; sympathetic nervous system; reactive hyperemia; hypoxia; phentolamine

CENTRAL NEURAL, LOCAL METABOLIC, and myogenic factors are the principal determinants of skeletal muscle blood flow and act to maintain tissue homeostasis and blood pressure during physiological stress (2, 19, 30). In exercising skeletal muscle, powerful local vasodilator mechanisms designed to increase blood flow and O2 delivery are counterbalanced by reflex-induced increases of sympathetic nerve activity that limit vasodilation and thereby prevent hypotension (30). Similarly, systemic hypoxia leads to skeletal muscle vasodilation despite an increase in sympathetic vasoconstrictor nerve activity and release of norepinephrine (22).

Metabolic vasodilators compete with neural vasoconstrictor activity by direct action on vascular smooth muscle or by interfering with sympathetic neural transmission (37). For example, it has been shown that the vasoconstrictor response to the exogenously administered {alpha}-adrenergic receptor agonist norepinephrine is attenuated in exercising muscle of animals and humans (1, 4, 8, 29, 36). However, unlike in exercise, the postjunctional {alpha}-adrenergic vasoconstrictor responsiveness of the forearm was reported to be intact during mild to moderate systemic hypoxia (9).

Aside from exercise hyperemia, a large increase in limb blood flow is also observed when blood flow is restored following temporary arterial occlusion (reactive hyperemia). The mechanisms underlying reactive hyperemia are incompletely understood, and an interplay of local factors such as release of vasodilator prostaglandins (5, 11), adenosine (5), nitric oxide (11), and myogenic factors (5, 18, 34) is thought to be important. To what extent basal sympathetic vasoconstrictor nerve activity attenuates reactive hyperemia is unclear.

It has been debated whether sympathetic tone affects the increase in limb blood flow noted during systemic hypoxia. Experimental data from animals and humans in support (14, 16, 35) and against (12, 28, 32) this possibility have been reported. Recently, Weisbrod et al. showed that regional blockade of {alpha}-adrenergic receptors by brachial artery infusion of phentolamine increased the forearm vasodilator responses to hypoxia by almost twofold (41).

The aim of this study was to determine the impact of regional sympathetic block on limb blood flow in resting human skeletal muscle subjected to the two distinct and potent vasodilator stimuli of limb ischemia and systemic hypoxia. In some prior studies, regional sympathetic block was achieved with bretylium tosylate administered via Bier block (15, 20). Because this agent is no longer available for human use, in this study we used the Bier block technique (13) in conjunction with the nonselective {alpha}-adrenergic receptor blocker phentolamine. Phentolamine has been used extensively as a sympatholytic in human investigations (10, 41, 43). For the Bier block, phentolamine was instilled into a deep forearm vein during a 20-min period of arterial occlusion achieved by inflation of a pneumatic cuff. Following reestablishment of blood flow and recovery from the ensuing reactive hyperemia, this allowed us to examine the effects of regional sympathetic block on the forearm blood flow (FBF) responses to regional and systemic vasodilator signals. Our data support the hypothesis that regional sympathetic block substantially enhances the vasodilator responses to ischemia and to systemic hypoxia.


   METHODS
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 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Subjects. Studies were performed in 22 healthy volunteers (14 men, 8 women), age 26 ± 1 yr (range 24–39 yr) with a weight of 73 ± 3 kg and a body mass index of 24 ± 1 kg/m2 (means ± SE). On arrival at the General Clinical Research Center, a routine history and physical examination was performed, and written, informed consent was obtained. All subjects were physically active, normotensive nonsmokers, and none was receiving chronic medications. Pregnant women were excluded from the study. Subjects avoided caffeine, alcohol, and exercise for 24 h before testing. The experimental protocol was approved by the Institutional Review Board at Hershey Medical Center.

Procedures and measurements. The studies were performed in a clinical research laboratory during the daytime hours at a room temperature of ~21°C. Two separate protocols were performed before and following regional sympathetic block in the nondominant forearm via Bier block using the nonspecific {alpha}-receptor antagonist phentolamine. Before instrumentation, forearm volume (from wrist to the olecranon) was determined by the water-displacement technique. The subjects were then placed in a supine position, and a Teflon catheter was inserted retrogradely into a deep antecubital vein of the nondominant (experimental) forearm. Throughout the experiment, the arm was kept at the level of the heart.

Heart rate was monitored by two-lead electrocardiogram. Blood pressure was measured with an automated sphygmomanometer (Dinamap, Critikon, Tampa, FL). Pneumatic cuffs (5 cm) were positioned at the wrist and just above the antecubital fossa (experimental forearm). In the hypoxia studies, minute ventilation (VE; l/min), end-tidal CO2 (CO2ET; Torr), and arterial oxyhemoglobin saturation (SaO2; %) were determined with a respiratory gas monitor (Ohmeda RGM 5250, Ohmeda), and chest movements were monitored via a strain-gauge pneumograph.

FBF was determined by Doppler ultrasound (ATL 5000; Philips Medical Systems, Bothell, WA), as described previously (25). A 5- to 12-MHz linear-array transducer was positioned over the brachial artery just above the pneumatic occlusion cuff. Mean blood velocity (MBV; cm/s) was measured at an insonation angle of ≤60° with a sample volume equal to the size of the artery (25). Vessel diameter was measured at baseline in a longitudinal view at the end of diastole as the distance between the near- and far-wall intima-media interfaces, and cross-sectional area was calculated as {pi}r2 (cm2), where r is vessel radius (cm). FBF (ml/min) was calculated as cross-sectional area x MBV x 60, and forearm vascular conductance (FVC) was calculated as FBF/mean arterial pressure (ml·min–1·mmHg–1; units). Baseline FBF was determined over ~3 min before each experimental condition. Skin blood flow (SBF; units) was measured with a laser-Doppler diode (Laserflo BPM, Vasomedics, St. Paul, MN) positioned over the volar surface of the forearm (22). MBV and SBF were recorded online at 100 Hz with a PowerLab system (AD Instruments, Castle Hill, Australia), and skin vascular conductance (SVC) was calculated as SBF/mean arterial pressure (units). The following interventions were then performed:

Protocol 1: reactive hyperemic blood flow. To maximize the reproducibility of sequential reactive hyperemic blood flow (RHBF) measurements, a "priming" maneuver was performed by inflating the upper arm cuff to suprasystolic pressure (250 mmHg) for 1 min (6, 26). Following an ~10-min recovery, basal FBF was determined. Before all FBF measurements, the wrist cuff was inflated to suprasystolic pressure (250 mmHg) to exclude blood flow to the hand, which predominantly consists of skin (21). The arm cuff was then inflated to suprasystolic pressure for 10 min, after which it was deflated and MBV was determined at 15-s intervals for 3 min (RHBF). The subjects then rested for ~15 min.

Protocol 2: systemic hypoxia. In this protocol, a tight-sealing facemask with separate valves for inspired and expired air was positioned to determine VE and CO2ET, and the ear probe was connected to monitor SaO2. Following acclimatization to the face mask and while breathing room air, baseline measurements of hemodynamic and ventilatory parameters and of FBF were made over ~3 min. The facemask was then connected to a hypoxic gas (inspired O2 fraction = 0.1), hemodynamic and ventilatory measurements were made continuously, and FBF measurements were made at ~5 and ~10 min of hypoxia. The facemask was then disconnected, and preparations began for the Bier block.

Phentolamine Bier block. In this procedure, the nonspecific {alpha}-receptor antagonist phentolamine was instilled into the forearm venous system during a 20-min period of occlusion of blood flow achieved with a pneumatic cuff inflated to 250 mmHg (13). To this end, the forearm was briefly elevated above the level of heart and was "exsanguinated" with a compressing Esmarch bandage. The arm cuff was then inflated, and the Esmarch bandage was removed. Phentolamine mesylate (0.12 mg/100 ml of forearm volume, diluted in 40 ml of saline) was then instilled into the venous cannula and was allowed to diffuse into the forearm tissue. At similar doses and administered intra-arterially, phentolamine has previously been shown to attenuate regional sympathetic vasoconstrictor tone without causing systemic effects (10, 41, 43). The volume of the instillate was equal to that in prior studies employing the Bier block (15, 20). Twenty minutes after administration of the drug, the cuff was deflated, and ~10 min after recovery from the ensuing reactive hyperemia, post-Bier block basal FBF was determined. Protocols 1 (RHBF) and 2 (hypoxia) were then repeated. In a separate group of subjects, we performed RHBF and hypoxia studies before and following a "control" Bier block procedure with saline.

Effectiveness of the phentolamine Bier block was established by determining the FBF response to immersion of 1 ft in ice water (cold pressor test) for 3 min before and at 15, 30, and 45 min following Bier block in five separate subjects. The cold pressor test is known to raise sympathetic vasoconstrictor nerve traffic and to produce limb vasoconstriction (38). Before phentolamine Bier block, foot immersion in ice water increased MAP from 87 ± 4 to 107 ± 10 mmHg, decreased FVC by 26 ± 8%, and demonstrated vasoconstriction in all subjects. At 15, 30, and 45 min following phentolamine Bier block, ice immersion increased FVC by 26 ± 4, 37 ± 12, and 19 ± 15%, respectively (all 5 subjects completed the 15- and 30-min trial, but only 4 completed the 45-min trial). Thus, in all subjects, the vasoconstriction was abolished or markedly attenuated, and this effect persisted at 45 min following Bier block.

Data analysis and statistics. Blood pressure, heart rate, and respiratory measurements (during hypoxia) were monitored continuously throughout the study. Baseline data represent average measurements obtained over ~3 min of basal conditions before each intervention. RHBF was determined as peak RHBF, and total blood flow for each minute was calculated by the trapezoidal integration method. Blood flow during hypoxia was averaged over ~2 min, during minutes 4 and 5 and minutes 9 and 10 of hypoxia, respectively. Comparisons of basal blood flow pre- and post-Bier block and of the responses of RHBF and of hypoxia before and after phentolamine Bier block were performed with paired t-tests or with repeated-measures analysis of variance as appropriate. Post hoc comparisons were performed by the simple effects method. Differences were considered statistically significant if P < 0.05. All values are reported as means ± SE.


   RESULTS
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 METHODS
 RESULTS
DISCUSSION
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Protocol 1: RHBF. The FBF and FVC responses to 10 min of forearm ischemia before and after phentolamine Bier block (n = 12) and before and after control Bier block with saline (n = 5) are shown in Table 1 and in Figs. 1 and 2. Throughout the RHBF maneuvers, blood pressure did not change [P = not significant (NS)]. Compared with pre-phentolamine, post-phentolamine basal FBF (P < 0.01) and vascular conductance (P < 0.01) were increased ~2.5-fold. In contrast, saline Bier block had no effect on basal FBF and FVC (P = NS). Compared with pre-phentolamine, post-phentolamine Bier block peak RHBF (P < 0.01) and peak FVC (P < 0.01) were markedly increased. Similarly, compared with pre-saline, post-saline Bier block peak RHBF (P < 0.01) and FVC (P < 0.05) were also increased. However, when analyzed minute by minute compared with pre-phentolamine, post-phentolamine Bier block RHBF was also increased in minute 2 (P < 0.05) and tended to be increased in minute 3 (P = 0.06). Post-saline Bier block, only the peak and 1-min values for FBF and FVC were elevated (P < 0.05), whereas the 2- and 3-min values were unchanged (P = NS).


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  		Table 1. Forearm blood flow and vascular conductance responses to limb ischemia pre- and post-Bier block with phentolamine or saline

 

Figure 1
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  		Fig. 1. Forearm blood flow responses (reactive hyperemia) in the experimental forearm before and after phentolamine Bier block. Post-phentolamine Bier block, peak forearm blood flow and blood flow throughout the period of reactive hyperemia was increased at all time points. The shaded area represents the initial (peak) portion of the reactive hyperemia that was affected by the Bier block procedure but not by phentolamine (see also Fig. 2).

 

Figure 2
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  		Fig. 2. Forearm blood flow responses (reactive hyperemia) in the experimental forearm before and after "control" Bier block with saline. Post-saline Bier block, peak forearm blood flow but not blood flow after the initial portion of the reactive hyperemia was increased. The shaded area represents the initial (peak) portion of the reactive hyperemia that was affected by the Bier block procedure but not by the drug administered (see also Fig. 1).

 
The effects of forearm ischemia pre- vs. post-phentolamine or -saline Bier block on SBF and SVC are shown in Table 2. On release of 10 min of forearm ischemia, SBF and SVC increased significantly. Compared with pre-phentolamine, post-phentolamine basal SBF (P < 0.05) and SVC (P < 0.05) were increased significantly, and peak SBF (P = 0.07) but not SVC (P = NS) tended to increase during reactive hyperemia. In contrast, basal SBF and the skin-reactive hyperemia responses were unchanged after compared with before saline Bier block. Of note, in all conditions, peak SBF was delayed compared with peak RHBF. Whereas peak RHBF consistently occurred within 15 s (Figs. 1 and 2), peak SBF was noted ~45 s after restoration of flow (Fig. 3).


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  		Table 2. Skin blood flow and vascular resistance responses to reactive hyperemia pre- and post-Bier block

 

Figure 3
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  		Fig. 3. Skin blood flow responses (reactive hyperemia) in the experimental forearm before and after phentolamine Bier block. Compared with total reactive hyperemia in the forearm (see Fig. 1), peak reactive hyperemia in skin was delayed.

 
Protocol 2: systemic hypoxia. The effects of hypoxia on hemodynamic and ventilatory parameters are shown in Table 3. Before and after Bier block, hypoxia was associated with reproducible increases in heart rate, VE, decreases of SaO2 and CO2ET, and small decreases of mean arterial pressure.


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  		Table 3. Mean arterial pressure, heart rate, minute ventilation, end-tidal CO2, and oxyhemoglobin saturation during hypoxia pre and post Bier block

 
The effects of systemic hypoxia on FBF and FVC are shown in Table 4 and Figs. 4 and 5. Before Bier block, hypoxia was associated with a statistically significant increase of FBF and FVC in the experimental and control groups. Compared with pre-phentolamine, in post-phentolamine Bier block, the increases of FBF (P < 0.05) and of FVC (P < 0.01) during hypoxia were markedly enhanced. In contrast, saline Bier block had no effect on the FBF and FVC responses to systemic hypoxia (P = NS).


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  		Table 4. Effects of systemic hypoxia on forearm blood flow (FBF) and vascular conductance (FVC) before phentolamine (n = 9) and after saline (n = 5) Bier block

 

Figure 4
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  		Fig. 4. Forearm blood flow responses to systemic hypoxia pre- and post-Bier block with phentolamine. Phentolamine Bier block significantly raised basal forearm blood flow and the blood flow responses to systemic hypoxia. *P < 0.05 pre- vs. post-Bier block.

 

Figure 5
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  		Fig. 5. Forearm blood flow responses to systemic hypoxia pre and post "control" Bier block with saline. No significant differences (P = not significant) were found in the forearm blood flow responses to hypoxia pre- vs. post-saline Bier block.

 
Before Bier block, in both groups, SBF and SVC did not change significantly during hypoxia (P = NS). Post-phentolamine Bier block, SBF (P < 0.05) but not SVC (P = NS) was increased significantly at minute 10 of hypoxia. Compared with pre-saline Bier block, no augmentation of SBF or SVC was noted post-saline (P = NS; Table 5).


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  		Table 5. Skin blood flow and vascular resistance during hypoxia pre- and post-Bier block

 
Before phentolamine Bier block, basal FBF determined ~30 min apart (i.e., before RHBF and before hypoxia) was similar (P = NS) at 35 ± 6 and 35 ± 6 ml/min, respectively, and was elevated (P < 0.05) at 82 ± 25 and 69 ± 14 ml/min, respectively, ~15 and ~45 min following phentolamine Bier block (n = 8). The corresponding data for FBF in the saline controls were 48 ± 12 and 54 ± 10 ml/min, respectively, before and 53 ± 9 and 54 ± 8 ml/min, respectively, following saline Bier block (P = NS; n = 5). Thus phentolamine but not saline Bier block resulted in a sustained (>45 min) increase in basal limb blood flow.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
In this report, we demonstrate that regional administration of the nonspecific {alpha}-adrenergic receptor antagonist phentolamine markedly enhances the vasodilator effects of ischemia and systemic hypoxia in skeletal muscle of the human forearm. This suggests that sympathetic vasoconstrictor nerve activity restrains vasodilation via an {alpha}-receptor-mediated mechanism. This finding highlights the competing nature of central and peripheral mechanisms that control skeletal muscle blood flow during physiological stress. An additional and intriguing finding is that, compared with peak forearm reactive hyperemia, peak skin reactive hyperemia is markedly delayed.

A unique aspect of our study is that regional sympathetic block was applied with a minimally invasive procedure that avoids arterial cannulation. The ~2.5-fold increase in basal blood flow noted after phentolamine Bier block but not saline closely mirrors the increase in blood flow noted in prior studies with intra-arterial infusions of the {alpha}-receptor antagonists phentolamine (10, 41, 43) and phenoxybenzamine (28) and also that noted in studies which employed a Bier block in conjunction with the norepinephrine reuptake inhibitor bretylium (15, 20). Because blood pressure was not decreased after the Bier block, we believe it is unlikely that a systemic effect of phentolamine was present. Collectively, our data suggest that the phentolamine Bier block may be a viable alternative to achieve regional sympathetic block in the human forearm.

Reactive hyperemia. Despite extensive investigation, the precise mechanism responsible for the hyperemic response following limb ischemia and the impact of sympathetic vasoconstrictor tone on this response are not well established. Reactive hyperemia is thought to be caused by physical and local metabolic factors that result from limb ischemia produced by transient arterial occlusion. Among metabolic vasodilator factors, prostaglandins (5, 11), adenosine (5), and nitric oxide (11) are thought to play a role. In addition, vascular myogenic tone, which is decreased in the collapsed arterial tree of the ischemic limb, is thought to contribute particularly to the early portion of the hyperemia on restoration of blood flow (5, 11, 34). Indeed, mechanosensitive vasodilator mechanisms that are independent of metabolic factors have been demonstrated in an isolated vascular preparation (18). Our data show that, for an identical ischemic stimulus (i.e., 10 min of blood flow occlusion), reactive hyperemia was markedly enhanced following compared with before phentolamine Bier block. This suggests that, in addition to its effect on basal blood flow, the sympathetic nervous system significantly restrains the hyperemia induced by limb ischemia. Although blood flow was significantly increased by the Bier block procedure in the phentolamine and saline groups in the first 15 s of hyperemia, post-phentolamine but not post-saline blood flow remained elevated during the later portions (i.e., following the initial 15 s) of the reactive hyperemia. Why peak blood flow was increased even in the post-saline group is not clear. It is conceivable that the prolonged 20-min period of circulatory arrest imposed by the Bier block procedure could have enhanced peak reactive hyperemia post-saline independent of any drug effect, possibly via an effect on myogenic tone. It is also possible that changes in electrolytes or other effects on the local tissue environment may have played a role. However, because basal blood flow, the blood flow response following the initial 15 s of reactive hyperemia, and blood flow before and during hypoxia were not affected by saline Bier block, the differences between the saline and phentolamine data are best explained by a specific effect of phentolamine on vascular {alpha}-receptors. Taken together, these data suggest that basal sympathetic vasoconstrictor tone substantially restrains the profound vasodilation induced by a sustained period of ischemia.

Our data further suggest that the effect of phentolamine on the skin circulation may contribute to a small degree to the augmentation of the forearm reactive hyperemia observed during regional sympathetic block. Interestingly, compared with the postocclusive time course of total FBF, the reactive hyperemia and subsequent recovery in the skin were delayed. In agreement with prior reports, peak FBF elicited by 10 min of arterial occlusion was noted within 15 s of restoration of flow (27, 40). In contrast, peak SBF occurred ~45 s after cuff release. The reason for the delay in peak skin reactive hyperemia and of its recovery is not well understood. Wilkin reported that the rate of rise to peak reactive hyperemia and the rate of recovery decrease with increasing duration of arterial occlusion (42). It was suggested that the decrease in both rates as a function of the duration of ischemia is consistent with viscoelastic characteristics of resistance vessels rather than changes in the concentration of hypothetical vasodilator metabolites produced during occlusion (42). The delayed recovery may also relate to the hyperemia-induced warming of the skin or, alternatively, to a "steal" syndrome due to more profound vasodilation in forearm muscle. Lastly, activation of sympathetic discharge to skin and its appendages due to an arousal effect of the reactive hyperemia may play a role independent of the vasodilator stimulus induced by ischemia (39).

Blood flow responses to hypoxia. It has been previously shown that acute hypoxia results in an increase of sympathetic vasoconstrictor outflow to muscle vascular beds (22, 31, 33), a concomitant increase in norepinephrine release (22), and skeletal muscle vasodilation (23, 28). Studies that examined the role of sympathetic vasoconstrictor tone reported that hypoxia-induced vasodilation was unaffected (28) or substantially enhanced (41) during intra-arterial infusion of the nonspecific {alpha}-receptor antagonists phenoxybenzamine (28) or phentolamine (41), respectively. Using intravenous administration of phentolamine via Bier block, our data support the recent conclusion by Weisbrod et al. that sympathetic vasoconstrictor nerve activity substantially masks the effects of hypoxia on vascular tone (41). Proposed mechanisms of hypoxia-induced skeletal muscle vasodilation in humans include epinephrine-mediated stimulation of beta-adrenergic receptors (41), release of nitric oxide (3, 7, 41) and/or adenosine (23, 24), and appear to be unmasked by regional sympathetic block.

Similar to the report by Weisbrod et al. (41) and in accordance with our laboratory's prior findings (22), we did not observe skin vasodilation during hypoxia. However, in agreement with the former report, post-phentolamine, a small increase in SBF was noted early during hypoxia (41). Thus skin vasodilation during hypoxia may be opposed by tonic {alpha}- adrenergic vasoconstriction. The nature of the vasodilator signal that was unmasked by regional sympathetic block during hypoxia in skin is not known.

Several limitations of our study should be discussed. First, the Bier block procedure itself required a 20-min period of ischemia, which is associated with a large transient reactive hyperemia and could augment a subsequent vasodilator stimulus. In fact, we noted increased peak blood flow and conductance but not flow responses to systemic hypoxia post- compared with pre-control Bier block (saline). Patterson and Whelan demonstrated that, of serial reactive hyperemias, the first one exhibits lower peak values than subsequent ones that are highly reproducible (26). As in prior studies (17) and in an attempt to optimize the reproducibility of sequential reactive hyperemias, we therefore used a 1-min priming maneuver before collecting RHBF data. Whether a longer priming maneuver would have prevented the augmentation of peak RHBF seen following sham Bier block with saline is unknown. However, for several reasons, we believe it is very unlikely that this issue interferes with the interpretation of our data. First, only phentolamine but not saline resulted in an increase of basal FBF. Second, only phentolamine but not saline resulted in an increase of reactive hyperemia after the first 15 s following restoration of flow. Third, only phentolamine but not saline enhanced the blood flow responses to systemic hypoxia. We should also acknowledge that our control group was small. However, as all but the initial portion of reactive hyperemia as well as the hypoxia data in our controls were nearly identical pre- and post-Bier block with saline, a much larger control group would be required to detect an effect of saline if present.

In conclusion, these data suggest that sympathetic vasoconstrictor nerve activity significantly restrains increases in skeletal muscle and cutaneous blood flow induced by local (forearm ischemia) and systemic (hypoxia) vasodilator stimuli. These data highlight the competing nature of central and peripheral mechanisms that control skeletal muscle blood flow during physiological stress in humans. The ability to preserve sympathetic vasoconstrictor control during activation of systemic or regional vasodilator mechanisms likely serves to prevent hypotension and consequent hypoperfusion of critical organs.


   GRANTS
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This work was supported in part by National Institute of Health Grants P01 HL-077670, R01 HL-068699, C06 RR-016499, and M01 RR-010732.


   ACKNOWLEDGMENTS
 
The authors thank the study subjects for participation in this project, the nursing staff in the GCRC for assistance with monitoring of the subjects, and to Jennie Stoner for expert secretarial assistance.


   FOOTNOTES
 

Address for reprint requests and other correspondence: U. A. Leuenberger, Penn State Heart and Vascular Institute, 500 Univ. Dr., Hershey, PA 17033 (e-mail: uleuenberger{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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 DISCUSSION
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 REFERENCES
 

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