Journal of Applied Physiology Millar Instruments
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

J Appl Physiol 92: 2019-2025, 2002. First published February 1, 2002; doi:10.1152/japplphysiol.01025.2001
8750-7587/02 $5.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow All Versions of this Article:
92/5/2019    most recent
01025.2001v1
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (25)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Eisenach, J. H.
Right arrow Articles by Joyner, M. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Eisenach, J. H.
Right arrow Articles by Joyner, M. J.
Vol. 92, Issue 5, 2019-2025, May 2002

Effects of chronic sympathectomy on vascular function in the human forearm

John H. Eisenach, Erin S. Clark, Nisha Charkoudian, Frank A. Dinenno, John L. D. Atkinson, Robert D. Fealey, Niki M. Dietz, and Michael J. Joyner

Departments of Anesthesiology, Neurosurgery, Neurology, and General Clinical Research Center, Mayo Clinic and Mayo Medical School, Rochester, Minnesota 55905


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

To determine whether endothelial function is altered by chronic surgical sympathectomy, we infused ACh, isoproterenol, nitroprusside (NTP), and the nitric oxide synthase inhibitor NG-mono-methyl-L-arginine (L-NMMA) into the brachial arteries of nine patients 5-64 mo after thoracic sympathectomy for hyperhidrosis. Age- and gender-matched controls were also studied. Forearm blood flow (FBF) was measured by venous occlusion plethysmography. Lower body negative pressure was used to assess reflex vasoconstrictor responses. Tyramine, which acts locally and causes norepinephrine release from sympathetic nerves, was also administered via the brachial artery. FBF at rest was 2.5 ± 0.4 ml · dl-1 · min-1 in the patients and 2.5 ± 0.3 ml · dl-1 · min-1 in the controls (P = 0.95). The normal vasoconstrictor responses to lower body negative pressure were abolished in the patients. By contrast, tyramine produced dose-dependent vasoconstriction in the patients that was identical to that of controls. The dose-response curves to ACh were similar in patients and controls, with maximum values of 19.3 ± 4.4 vs. 25.5 ± 2.8 ml · dl-1 · min-1, respectively. L-NMMA reduced baseline FBF similarly and reduced the maximal FBF response to ACh in both groups (patients 8.9 ± 3.5 vs. controls 9.7 ± 2.5 ml · dl-1 · min-1). The vasodilation to isoproterenol was similar and blunted to the same extent in both groups by L-NMMA. The responses to NTP in patients and controls were similar and not affected by L-NMMA. We conclude that, in humans, chronic surgical sympathectomy does not cause major disruptions in vascular function in the forearm. The normal vasoconstrictor responses to tyramine indicate that there were viable sympathetic nerves in the forearm that were not engaged by LBNP.

forearm blood flow; endothelium; vasodilation; nitric oxide; tyramine


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

IMMEDIATELY AFTER SURGICAL sympathectomy, forearm blood flow (FBF) increases dramatically because of a lack of sympathetic vasoconstriction. However, after a few weeks, resting blood flow returns to presympathectomy levels (2). The mechanisms underlying this response are unclear. One possible explanation might be loss of endothelial NO release. Previous studies have shown that chronic pharmacological sympathectomy in rats with guanethidine nearly abolishes aortic endothelial NO synthase (eNOS) as detected by immunocytochemistry (1), and surgical sympathectomy blunts endothelial function in the rabbit carotid artery (16, 17). By contrast, a study in humans who had undergone thoracic sympathectomy showed that systemic eNOS inhibition caused more vasoconstriction in the sympathectomized forearm than the normally innervated calf, implying enhanced NO synthesis or biological activity in the sympathectomized limb (19). Additionally, in vivo studies in rats have found no functional change in endothelium-dependent vasodilation after chemical sympathectomy (27). Finally, in dogs sympathectomy does not alter endothelium-dependent vasodilator responses in isolated femoral artery rings, suggesting that endothelial function is unchanged (18). The reasons for these differing results are obscure.

Additional indirect evidence on this topic in humans comes from a study conducted in the 1950s (3). In this study, the normal forearm vasodilator response to mental stress was absent months or years after surgical sympathectomy. Later studies showed that the forearm dilator responses to mental stress and other sympathoexcitatory maneuvers were NO dependent but probably not caused by vasodilator nerves, suggesting an important role for the vascular endothelium (7, 8, 11, 20, 25). When the older data are viewed in light of the newer findings, the implication is that endothelial function in the human forearm is impaired after surgical sympathectomy (15). This interpretation is consistent with the animal data from the studies showing blunted endothelial function after sympathectomy (1, 16, 17).

With this information as background, the purpose of our study was to test the hypothesis that endothelium-mediated vasodilation in the forearm will be blunted in patients who have undergone surgical sympathectomy. To test this hypothesis, we performed pharmacological studies of endothelial function in the forearms of sympathectomized patients and control subjects.


    MATERIALS AND METHODS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Subjects. Nine patients (8 men, 1 woman, ages 25-45 yr) were studied 5-64 mo after bilateral endoscopic thoracic sympathectomy for palmar hyperhidrosis (26). They were compared with age- and gender-matched controls. Both groups were studied in the same laboratory environment January through March of 2001. The protocols were approved by the Institutional Human Subjects Committee, and each patient and subject gave written informed consent. Subject characteristics are shown in Table 1. The female patient and control had negative serum pregnancy tests within 12 h before participation. All sympathectomy patients reported anhidrosis of the upper extremities. One patient was on low-dose amitriptyline (discontinued 24 h before the study) for bothersome hyperhidrosis of the lower extremities. Another patient with mild narcolepsy was taking pemoline, discontinued 4 days before the study. One patient and one control subject with hypertension were taking atenolol, which was discontinued 24 h before the study.

                              
View this table:
[in this window]
[in a new window]
  		Table 1.   Subject characteristics

Subject instrumentation. Heart rate was monitored by use of a five-lead electrocardiogram. A 20-gauge, 5-cm catheter was placed in the brachial artery of the nondominant arm under aseptic conditions after local anesthesia (1% lidocaine). A three-port connector was placed in series with a catheter-transducer system so that drugs could be infused and arterial pressure measured simultaneously (7).

FBF. FBF was measured by use of venous occlusion plethysmography with a mercury-in-Silastic strain gauge placed around the nondominant forearm at its greatest circumference (10). During recording, a wrist cuff was continuously inflated to suprasystolic pressure (250 mmHg) to occlude arterial blood flow to the hand while a venous occlusion cuff around the upper arm was inflated to 50 mmHg for 7.5 of every 15 s, providing one blood flow measurement every 15 s. FBF values were expressed as ml · 100 ml tissue-1 · min-1.

LBNP. To confirm that the patients were effectively sympathectomized, lower body negative pressure (LBNP) was used to cause graded venous pooling and activate the sympathetic nervous system (14, 24). Each subject was placed in a LBNP box before arterial cannulation. Arterial catheter placement was followed by 15 min of rest. Blood flow was then measured for 2 min at rest, followed by 2 min at 10, 20, and 30 mmHg of negative pressure.

Drug infusion protocol and drug doses. To normalize drug doses, each subject's forearm volume was measured by water displacement. All study drugs were administered at rates of 2-3 ml/min. After LBNP, a cumulative FBF dose-response curve to intra-arterial tyramine was performed. After this, incremental infusions of sodium nitroprusside (NTP), isoproterenol, and ACh were administered before and after NG-mono-methyl-L-arginine (L-NMMA; Fig. 1). Each dose of each drug was administered for 2-3 min, and the dose-response determinations were separated by 20 min of quiet rest.


View larger version (11K):
[in this window]
[in a new window]
  		Fig. 1.   Timeline of protocol for sympathectomized patients and controls. After tyramine, 3 vasodilators [sodium nitroprusside (NTP), isoproterenol, and ACh] were individually administered and then given in reverse order after a bolus and continuous infusion of NG-mono-methyl-L-arginine (L-NMMA). FBF, forearm blood flow; t, time.

Tyramine was used to test for residual sympathetic function because it evokes norepinephrine "leakage" from neuronal vesicles and consequent diffusion of norepinephrine out of the nerve terminal (9, 31). Tyramine also has no intrinsic vasoconstricting properties (5). It was infused for 3 min at 3, 6, and 12 µg · dl tissue-1 · min-1 (9). To test NO-mediated endothelium-independent vasorelaxation, the NO donor sodium NTP was infused for 2 min at 0.25, 0.5, 1.0, and 2.0 µg · dl tissue-1 · min-1 (7, 8). To test beta -adrenergic receptor-mediated vasodilation, isoproterenol was infused for 2 min at 1.0, 3.0, 6.0, and 12.0 ng · dl tissue-1 · min-1 (6). To test endothelium-dependent vasodilation, ACh was infused for 2 min at 1.0, 2.0, 4.0, and 8.0 µg · dl tissue-1 · min-1 (32).

After the initial drug infusions and return of forearm flow to baseline levels, the wrist cuff was reinflated and the eNOS inhibitor L-NMMA (50 mg) was infused over 10 min while FBF was measured (7, 8, 32). This was followed by a "maintenance" dose of L-NMMA (1 mg/min) throughout the remainder of the protocol. Administration of the three vasodilating drugs was then repeated in reverse order (ACh, isoproterenol, and NTP). We reasoned that if any differences between the patients and controls were due to NO production, then the responses after L-NMMA would be similar. The order of drug administration was not randomized so that the repeat doses of ACh could be given immediately after L-NMMA, so that we could immediately assess the magnitude of the NOS inhibition.

Data analysis. Data were digitized at 200 Hz and stored on computer. Data were analyzed off-line with signal processing software (Windaq; Dataq Instruments, Akron, OH). FBF was determined from the derivative of the forearm plethysmogram during the last 2 min of each increment of LBNP and during the last minute of each drug dose. Heart rate was derived from the electrocardiogram waveform. Mean arterial pressure (MAP) was derived from the arterial pressure waveform. Forearm vascular conductance (FVC) was calculated as (FBF/MAP) × 100 and expressed as arbitrary units. These units were used because they are quantitatively similar to standard FBF values (25). For the LBNP data, FVC was reported because it accounts for the modest decreases in MAP during LBNP. For the remainder of the study, FBF was reported because it was the primary measured variable in the pharmacological dose-response curves and because there were negligible changes in MAP during the isolated forearm drug infusions.

Statistics. For subject characteristics (Table 1), the two groups were compared by using the two-sample t-test for all variables except gender, which was compared by using Fisher's exact test. Repeated measures analysis of variance (ANOVA) was used to assess differences between sympathectomy and control subjects at various doses of LBNP and the four different drug infusion conditions (tyramine, NTP, isoproterenol, and ACh). For these analyses, either FVC or FBF was the dependent variable, sympathectomy was an independent cross-classification variable, and dose was the repeated factor. In addition, for NTP, isoproterenol, and ACh, additional repeated-measures models were used in which the presence or absence of L-NMMA was included as a second repeated factor. In all cases, data are reported as means ± SE. Significance was set at the P < 0.05 level.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Selected subject characteristics are shown in Table 1. Baseline FBF and FVC were similar in both groups. Body weight was higher and blood pressure tended to be higher in patients vs. controls.

Vasoconstrictor responses. In the sympathectomy patients, FBF was 2.5 ± 0.4 ml · dl-1 · min-1 at baseline and 2.3 ± 0.3 ml · dl-1 · min-1 at -30 mmHg LBNP. In control subjects, FBF was 2.5 ± 0.3 ml · dl-1 · min-1 at baseline and decreased to 1.3 ± 0.2 ml · dl-1 · min-1 at -30 mmHg LBNP. In the patients, MAP was 105 ± 4.4 mmHg at baseline and 99 ± 3.5 mmHg at -30 mmHg LBNP. In control subjects, MAP was 99 ± 3.7 mmHg at baseline and 94 ± 3.7 mmHg at -30 mmHg LBNP. Figure 2 displays the percent change from baseline FVC in response to changes in LBNP. A decline in FVC was observed with increasing LBNP for the control group whereas FVC remained unchanged in the sympathectomy group (P < 0.001 for the main effects of dose and sympathectomy, and P = 0.007 for the sympathectomy-by-dose interaction). By contrast, tyramine reduced FBF equally in both groups at every dose as shown in Fig. 3 (P < 0.001 for dose, P = 0.618 for sympathectomy, and P = 0.699 for the dose-by-sympathectomy interaction). At maximal concentration of tyramine (12 µg · dl tissue-1 · min-1), FBF fell to 1.2 ± 0.1 ml · dl-1 · min-1 in patients and 1.2 ± 0.2 ml · dl-1 · min-1 in controls.


View larger version (15K):
[in this window]
[in a new window]
  		Fig. 2.   Average forearm vascular responses to lower body negative pressure (LBNP) in sympathectomized individuals and control subjects. A decline in forearm vascular conductance (FVC) was observed with increasing LBNP for the control group, whereas FVC remained unchanged in the sympathectomy group. To supplement the repeated-measures analysis, the paired t-test was used for each group to compare FVC to baseline at each dose level. *Significant (P < 0.05) differences from baseline.



View larger version (16K):
[in this window]
[in a new window]
  		Fig. 3.   FBF in response to 3 doses of tyramine, which evokes norepinephrine release from sympathetic nerves. From repeated-measures ANOVA, FBF was found to decrease with increasing doses of tyramine (P < 0.001). There was no significant evidence to suggest that this effect differed for sympathectomy vs. control (P = 0.618 and P = 0.699 for the main effect of sympathectomy and the sympathectomy-by-dose interaction). FBF was similar in the patients and controls throughout.

Vasodilator responses. There were no significant differences between patients and controls in the endothelium-dependent forearm vasodilation to ACh (P < 0.001 for dose, P = 0.523 for sympathectomy, and P = 0.348 for the dose-by-sympathectomy interaction). As can be seen in Fig. 4, the dose-response relationships were similar between the two groups. At the highest ACh dose (8.0 µg · dl tissue-1 · min-1), maximal FBF response was 19.3 ± 4.4 ml · dl-1 · min-1 in the patients vs. 25.5 ± 2.8 ml · dl-1 · min-1 in the controls. L-NMMA reduced resting FBF from 3.6 ± 0.3 to 1.8 ± 0.2 ml · dl-1 · min-1 in the sympathectomy patients and 3.2 ± 0.3 to 1.9 ± 0.3 ml · dl-1 · min-1 in controls with no differences observed between groups. Furthermore, maximal FBF response to ACh was reduced to 8.9 ± 3.5 in patients vs. 9.7 ± 2.5 ml · dl-1 · min-1 in controls. The effect of L-NMMA was not significantly different for sympathectomy patients compared with controls (i.e., no significant interactions were detected). The sympathectomy patients who were taking pemoline and amitriptyline did not differ qualitatively from the other patients or controls.


View larger version (24K):
[in this window]
[in a new window]
  		Fig. 4.   FBF in response to ACh before and after endothelial nitric oxide synthase (eNOS) inhibition with L-NMMA. In the absence of L-NMMA, there was a significant dose effect (P < 0.001) with no evidence to suggest that this effect differed for sympathectomy (Symp) vs. control (Ctrl) (P = 0.523 and P = 0.348 for the main effect of sympathectomy and the sympathectomy-by-dose interaction). From repeated-measures ANOVA with dose and L-NMMA included as the repeated factors, the main effects and 2-way interaction effect of dose and L-NMMA were highly significant (P < 0.001 in all cases), indicating that FBF increased with higher doses but that this effect was reduced in the presence of L-NMMA. There was no evidence to suggest that these effects were different between sympathectomy and control groups (i.e., no significant interactions with sympathectomy).

There also were no differences between groups in the forearm vasodilation responses to isoproterenol (P < 0.001 for dose, P = 0.942 for sympathectomy, and P = 0.913 for the dose-by-sympathectomy interaction; see Fig. 5). In the absence of L-NMMA, maximal FBF in response to isoproterenol was 14.0 ± 2.4 ml · dl-1 · min-1 in the patients vs. 13.8 ± 1.3 ml · dl-1 · min-1 in the controls. After L-NMMA, the peak vasodilator response to isoproterenol was reduced to the same extent in the patients (10.3 ± 1.4 ml · dl-1 · min-1) and in the controls (10.1 ± 0.9 ml · dl-1 · min-1).


View larger version (22K):
[in this window]
[in a new window]
  		Fig. 5.   Sympathectomy does not alter beta -adrenergic receptor-mediated forearm vasodilation. From repeated-measures ANOVA, the main effect and 2-way interaction of dose and L-NMMA were highly significant (P < 0.001 in all cases), indicating that FBF increased with higher doses but that this effect was reduced in the presence of L-NMMA. There was not evidence to suggest that these effects were different between sympathectomy and control groups. Iso, isoproterenol.

Figure 6 shows the FBF responses to sodium NTP in patients and controls. There was no difference in endothelium-independent forearm vasodilation (P < 0.001 for dose, P = 0.444 for sympathectomy, and P = 0.516 for the dose-by-sympathectomy interaction). Before L-NMMA, at the highest NTP dose (2.0 µg · dl tissue-1 · min-1), FBF was 18.8 ± 3.3 ml · dl-1 · min-1 in the sympathectomy group vs. 20.2 ± 1.4 ml · dl-1 · min-1 in the control group. After L-NMMA, there was no change in maximal FBF to NTP both within and between the sympathectomy patients (19.9 ± 2.3 ml · dl-1 · min-1) and controls (23.8 ± 1.6 ml · dl-1 · min-1).


View larger version (22K):
[in this window]
[in a new window]
  		Fig. 6.   Dose response curves to nitroprusside show that sympathectomy does not alter vascular smooth muscle integrity. From repeated-measures ANOVA, the main effect and 2-way interaction of dose and L-NMMA were highly significant (P < 0.001 in all cases), indicating that FBF increased with higher doses, and this effect was unchanged in the presence of L-NMMA. There was not evidence to suggest that these effects were different between sympathectomy and control groups.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

There are four main findings of our study. First, endothelium-dependent forearm vasodilation was neither augmented or attenuated in humans months or years after endoscopic thoracic sympathectomy. Nitric oxide synthase inhibition by intra-arterial L-NMMA also decreased basal FBF and markedly inhibited the response to ACh to a similar extent in both patients and controls. This indicates that endothelial function was not altered in a major way by surgical sympathectomy. Second, beta -adrenergic vasodilation was also similar in the patients and controls, and L-NMMA partially inhibited the dilator response to isoproterenol. Third, vascular smooth muscle responsiveness to NTP (and hence NO) was preserved after sympathectomy. Fourth, sympathectomy patients showed a normal (and puzzling) vasoconstrictor response to tyramine in spite of the fact that they do not report sweating and do not demonstrate vasoconstriction during LBNP. The physiological implications of these findings and the limitations associated with our experimental design will now be discussed in detail.

Sympathectomy and endothelial function. Our patients' normal responses to both ACh and L-NMMA are at odds with the animal studies that showed either nearly undetectable levels of eNOS after chemical sympathectomy with guanethidine or blunted vasorelaxation to endothelial stimulation after surgical sympathectomy (1, 16, 17). One possible explanation is that the sympathectomies generated in the models were more "complete" than in the patients. In view of the absent constrictor responses to LBNP but the preserved constrictor responses to tyramine, it seems reasonable to speculate that the patients retained or regenerated some functional postganglionic sympathetic nerves in their forearms. However, it appears that these nerves could not be activated by normal baroreflex (or thermoregulatory) mechanisms. This possibility was raised in the 1940s, but, in contrast to our patients, the patients studied earlier had physiological signs (sweating) consistent with the reinnervation (4). In view of our findings with tyramine, we speculate that the "normal" trophic interactions between the sympathetic nerves and endothelium were still present in the patients we studied.

Our findings that endothelial function was not altered by sympathectomy are also at odds with Lepori et al. (19). These authors reported that forearm vasoconstrictor responses during systemic (i.e., whole body) infusion of L-NMMA were augmented (in comparison to the nonsympathectomized calf) in patients who have undergone thoracic sympathectomy. They interpreted their data to suggest enhanced NO synthesis or bioavailability after sympathectomy. However, the increase in arterial blood pressure during systemic L-NMMA could have evoked a baroreflex-mediated reduction in sympathetic outflow to the calf but not the forearm in these patients (12). This means that the constriction caused by L-NMMA was unopposed in the forearm but that it was probably offset by sympathetic withdrawal in the calf. Thus the greater forearm vasoconstriction observed by Lepori et al. was probably not due to greater NO "tone" after sympathectomy. Along these lines, our results seem most consistent with the experiments in rats and dogs that showed unchanged ACh-evoked vasodilation after either chemical or surgical sympathectomy (18, 27). Finally, because the dilator responses to the NO donor NTP were similar in the patients and controls, it is unlikely that our results could be explained by differences in how the vessels responded to NO.

Responses to tyramine and isoproterenol. As discussed earlier, the preserved vasoconstrictor responses to tyramine in the absence of vasoconstriction to LBNP suggest that there was at least some viable postganglionic sympathetic innervation in the forearm after sympathectomy. This conclusion is supported by the isoproterenol dose-response curves. If there had been a complete absence of sympathetic innervation, then it would have been reasonable to expect augmented beta 2-mediated vasodilation in the patients as a result of upregulation of beta -receptors.

In this context, we can only speculate as to what mechanisms might be preserving the postganglionic sympathetic nerves. First, it is possible that T2 sympathectomy only disconnects the vasoconstrictor nerves to the forearm from cardiovascular and thermoregulatory reflexes and that the postsynaptic nerves to the forearm are sustained from another level of the sympathetic chain or from other neural structures (22, 29). If this occurs, it may take some time because there is typically marked vasodilation after sympathectomy with a return of vascular tone over several weeks (2). This may also explain why therapeutic sympathectomies for various clinical syndromes are initially effective but fail over time (21, 23, 28). A second mechanism that might sustain the postganglionic nerves after sympathectomy is the venoarteriolar axon reflex (13). This is a powerful reflex that acts locally to cause norepinephrine release when the limb veins are distended. This reflex is retained in patients with spinal cord lesions, but it is not known whether it remains active in patients similar to those we studied (13). Whatever the mechanism, it would appear that ganglionic connections that respond to baroreflex input were destroyed but that at least some postganglionic neurons that could be stimulated by tyramine remained functional.

Finally, it should be noted that in a previous study conducted many years ago, one sympathectomy patient received intra-arterial tyramine and showed no vasoconstrictor response (9). This raises the possibility that the older surgical techniques differ from the approach used in the patients we studied (26, 30). If this were the case, then any trophic interactions between the sympathetic nerves and endothelium might have been eliminated with at least one of the older techniques. This would then explain the previously noted absence of vasodilator responses now thought to be mediated by endothelial NO release (3). However, the technique used in our patients results in an almost immediate rise in finger temperature to 36°C that falls over several weeks, and this response is consistent with the earlier observations on the time course of blood flow changes after surgical sympathectomy (2).

Limitations. There are several limitations that should be noted. First, the patients had higher baseline blood pressure levels and tended to be heavier. These two factors can cause blunted vasodilator responses to ACh and might explain why the peak blood flow response to ACh tended to be lower in the patients. In this context, these differences might have reached significance had we studied more subjects, but the patients still had robust blood flow responses to ACh. The second major limitation is that the baseline flows after L-NMMA (but before the second isoproterenol or NTP trials) tended to drift upward. This suggests that the maintenance dose of L-NMMA was not effective. However, the blood flow responses to isoproterenol after L-NMMA were still blunted in a manner consistent with previous reports from the literature, suggesting adequate NOS inhibition throughout the second half of the study (5). A more likely explanation for this drift is that the baseline flows did not return to their absolute minimum during the 20-min rest period between administration of the various vasodilator drugs.

In summary, our current observations suggest that loss of endothelial function is not responsible for the return of tone that occurs in the forearm weeks and months after surgical sympathectomy. Our observations also either refute the idea that there are major trophic interactions between the sympathetic nerves and vascular endothelium in humans or suggest that any trophic relationship between the sympathetic nerves and the vascular endothelium was somehow maintained in the absence of functional thermoregulatory and baroreflex-mediated connections between the CNS and forearm sympathetic nerves.


    ACKNOWLEDGEMENTS

The time and effort put forth by the subjects who participated in our studies are greatly appreciated. The authors also appreciate the excellent secretarial assistance of Janet Beckman, the superb technical assistance of Karen Krucker and Shelly Roberts, and all of the hard work contributed by our statistician, Darrell R. Schroeder.


    FOOTNOTES

This work was supported by National Institutes of Health Grants HL-46493, NS-32352, RR-00585, NRSA AR/HL-08610, and NRSA AG-05912, and by the Mayo Foundation.

Address for reprint requests and other correspondence: M. J. Joyner, Dept. of Anesthesia Research, Mayo Clinic and Foundation, 200 First St. SW, Rochester, MN 55905 (E-mail: joyner.michael{at}mayo.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.

First published February 1, 2002;10.1152/japplphysiol.01025.2001

Received 11 October 2001; accepted in final form 20 January 2002.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

1.   Aliev, G, Ralevic V, and Burnstock GG. Depression of endothelial nitric oxide synthase but increased expression of endothelin-1 immunoreactivity in rat thoracic aortic endothelium associated with long-term, but not short-term, sympathectomy. Circ Res 79: 317-323, 1996.

2.   Barcroft, H, and Walker AJ. Return of tone in blood vessels of the upper limb after sympathectomy. Lancet i: 1035-1039, 1949.

3.   Blair, DA, Glover WE, Greenfield ADM, and Roddie IC. Excitation of cholinergic vasodilator nerves to human skeletal muscles during emotional stress. J Physiol (Lond) 148: 633-647, 1959.

4.   Boyd, JD, and Monro PAG Partial retention of autonomic function after paravertebral sympathectomy. Lancet ii: 892-895, 1949.

5.   Brandao, F, Monteiro JG, and Osswald W. Differences in the metabolic fate of noradrenaline released by electrical stimulation or by tyramine. Naunyn Schmiedebergs Arch Pharmacol 305: 37-40, 1978.

6.   Dawes, M, Chowienczyk PJ, and Ritter JM. Effects of inhibition of the L-arginine/nitric oxide pathway on vasodilation caused by beta -adrenergic agonists in human forearm. Circulation 95: 2293-2297, 1997.

7.   Dietz, NM, Rivera JM, Eggener SE, Fix RT, Warner DO, and Joyner MJ. Nitric oxide contributes to the rise in forearm blood flow during mental stress in humans. J Physiol (Lond) 480: 361-368, 1994.

8.   Dietz, NM, Engelke KA, Samuel TT, Fix RT, and Joyner MJ. Evidence for nitric oxide mediated sympathetic forearm vasodilatation in humans. J Physiol (Lond) 498: 531-540, 1997.

9.   Frewin, DB, and Whelan RF. The mechanism of action of tyramine on the blood vessels of the forearm in man. Br J Pharmacol 33: 105-116, 1968.

10.   Greenfield, ADM, Whitney RJ, and Mowbray JF. Methods for the investigation of peripheral blood flow. Br Med Bull 19: 101-109, 1963.

11.   Halliwill, JR, Lawler LA, Eickhoff TJ, Dietz NM, Nauss LA, and Joyner MJ. Forearm sympathetic withdrawal and vasodilatation during mental stress in humans. J Physiol (Lond) 504: 211-220, 1997.

12.   Hansen, J, Jacobsen TN, and Victor RG. Is nitric oxide involved in the tonic inhibition of central sympathetic outflow in humans? Hypertension 24: 439-444, 1994.

13.   Henriksen, O, and Sejrsen P. Local reflex in microcirculation in human skeletal muscle. Acta Physiol Scand 99: 19-26, 1977.

14.   Johnson, JM, Rowell LB, Niederberger M, and Eisman MM. Human splanchnic and forearm vasoconstrictor responses to reductions of right atrial and aortic pressures. Circ Res 34: 515-524, 1974.

15.   Joyner, MJ, and Halliwill JR. Sympathetic vasodilatation in human limbs. J Physiol (Lond) 526: 471-480, 2000.

16.   Kars, HZ, Utkan T, Sarioglu Y, and Yaradanakul V. Selective inhibition of endothelium-dependent relaxation by sympathectomy in rabbit carotid artery rings in vitro. Methods Find Exp Clin Pharmacol 15: 35-40, 1993.

17.   Kaya, T, Utkan T, Sarioglu Y, and Goksel M. Altered endothelium-mediated relaxation by sympathectomy in isolated rabbit carotid artery rings. Methods Find Exp Clin Pharmacol 17: 369-375, 1995.

18.   Komori, K, Takeuchi K, Ohta S, Funahashi S, Ishida M, Matsumoto T, Onohara T, Kume M, and Sugimachi K. Properties of endothelium and smooth muscle cells in canine femoral arteries after lumbar sympathectomy. Eur J Surg 165: 1086-1090, 1999.

19.   Lepori, M, Sartori C, Duplain H, Nicod P, and Scherrer U. Sympathectomy potentiates the vasoconstrictor response to nitric oxide synthase inhibition in humans. Cardiovasc Res 43: 739-743, 1999.

20.   Lindqvist, M, Davidsson S, Hjemdahl P, and Melcher AA. Sustained forearm vasodilation in humans during mental stress is not neurogenically mediated. Acta Physiol Scand 158: 7-14, 1996.

21.   Lowell, RC, Gloviczki P, Cherry KJ, Jr, Bower TC, Hallett JW, Jr, Schirger A, and Pairolero PC. Cervicothoracic sympathectomy for Raynaud's syndrome. Int Angiol 12: 168-172, 1993.

22.   Murray, JG, and Thompson JW. Collateral sprouting in response to injury of the autonomic nervous system, and its consequences. Br Med Bull 13: 213-219, 1957.

23.   Nicholson, ML, Dennis MJ, and Hopkinson BR. Endoscopic transthoracic sympathectomy: successful in hyperhidrosis but can the indications be extended? Ann R Coll Surg Engl 76: 311-314, 1995.

24.   Rea, RF, and Wallin BG. Sympathetic nerve activity in arm and leg muscles during lower body negative pressure in humans. J Appl Physiol 66: 2778-2781, 1989.

25.   Reed, AS, Tschakovsky ME, Minson CT, Halliwill JR, Torp KD, Nauss LA, and Joyner MJ. Skeletal muscle vasodilatation during sympathoexcitation is not neurally mediated in humans. J Physiol (Lond) 525: 253-262, 2000.

26.   Reisfeld, R, Nguyen R, and Pnini A. Endoscopic thoracic sympathectomy for treatment of essential hyperhidrosis syndrome: experience with 650 patients. Surg Laparosc Endosc Percutan Tech 10: 5-10, 2000.

27.   Sander, M, Hansen PG, and Victor RG. Sympathetically mediated hypertension caused by chronic inhibition of nitric oxide. Hypertension 26: 691-695, 1995.

28.   Schwartzman, RJ, Liu JE, Smullens SN, Hyslop T, and Tahmoush AJ. Long-term outcome following sympathectomy for complex regional pain syndrome type 1 (RSD). J Neurol Sci 150: 149-152, 1997.

29.   Skoog, T. Ganglia in the communicating rami of the cervical sympathetic trunk. Lancet ii: 457-460, 1947.

30.   Smithwick, RH. The problem of producing complete and lasting sympathetic denervation of the upper extremity by preganglionic section. Ann Surg 112: 1085-1100, 1940.

31.   Takauchi, Y, Yamazaki T, and Akiyama T. Tyramine-induced endogenous noradrenaline efflux from in situ cardiac sympathetic nerve ending in cats. Acta Physiol Scand 168: 287-293, 2000.

32.   Vallance, P, Collier J, and Moncada S. Effects of endothelium-derived NO on peripheral arteriolar tone in man. Lancet 2: 997-1000, 1989.

J APPL PHYSIOL 92(5):2019-2025
8750-7587/02 $5.00 Copyright © 2002 the American Physiological Society


This article has been cited by other articles:


Home page
 HypertensionHome page
W. T. Nicholson, B. Vaa, C. Hesse, J. H. Eisenach, and M. J. Joyner
Aging Is Associated With Reduced Prostacyclin-Mediated Dilation in the Human Forearm
Hypertension, June 1, 2009; 53(6): 973 - 978.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
D. S. Goldstein
Genotype and Vascular Phenotype Linked by Catecholamine Systems
Circulation, January 29, 2008; 117(4): 458 - 461.
[Full Text] [PDF]

Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
A. Basu, N. Charkoudian, W. Schrage, R. A. Rizza, R. Basu, and M. J. Joyner
Beneficial effects of GLP-1 on endothelial function in humans: dampening by glyburide but not by glimepiride
Am J Physiol Endocrinol Metab, November 1, 2007; 293(5): E1289 - E1295.
[Abstract] [Full Text] [PDF]

Home page
 Ann. Thorac. Surg.Home page
E. G. Lowe, P. D. Allmendinger, and R. Lowe
Cold Sensitivity as a New Side Effect After Sympathicotomy for Hyperhidrosis
Ann. Thorac. Surg., December 1, 2005; 80(6): 2356 - 2358.
[Abstract] [Full Text] [PDF]

Home page
 Ann. Thorac. Surg.Home page
C. T. Klodell, E. B. Lobato, J. L. Willert, and N. Gravenstein
Oximetry-Derived Perfusion Index for Intraoperative Identification of Successful Thoracic Sympathectomy
Ann. Thorac. Surg., August 1, 2005; 80(2): 467 - 470.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
M. W. P. Bleeker, M. Kooijman, G. A. Rongen, M. T. E. Hopman, and P. Smits
Preserved contribution of nitric oxide to baseline vascular tone in deconditioned human skeletal muscle
J. Physiol., June 1, 2005; 565(2): 685 - 694.
[Abstract] [Full Text] [PDF]

Home page
 Mayo Clin Proc.Home page
J. H. Eisenach, J. L. D. Atkinson, and R. D. Fealey
Hyperhidrosis: Evolving Therapies for a Well-Established Phenomenon
Mayo Clin. Proc., May 1, 2005; 80(5): 657 - 666.
[Abstract] [PDF]

Home page
 J. Physiol.Home page
S. Durand, S. L. Davis, J. Cui, and C. G. Crandall
Exogenous nitric oxide inhibits sympathetically mediated vasoconstriction in human skin
J. Physiol., January 15, 2005; 562(2): 629 - 634.
[Abstract] [Full Text] [PDF]

Home page
 Anesth. Analg.Home page
J. H. Eisenach, T. L. Pike, D. E. Wick, N. M. Dietz, R. D. Fealey, J. L. D. Atkinson, and N. Charkoudian
A Comparison of Peripheral Skin Blood Flow and Temperature During Endoscopic Thoracic Sympathotomy
Anesth. Analg., January 1, 2005; 100(1): 269 - 276.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
A. S. Reed, N. Charkoudian, A. Vella, P. Shah, R. A. Rizza, and M. J. Joyner
Forearm vascular control during acute hyperglycemia in healthy humans
Am J Physiol Endocrinol Metab, March 1, 2004; 286(3): E472 - E480.
[Abstract] [Full Text]

Home page
 J. Physiol.Home page
F. A Dinenno and M. J Joyner
Blunted sympathetic vasoconstriction in contracting skeletal muscle of healthy humans: is nitric oxide obligatory?
J. Physiol., November 15, 2003; 553(1): 281 - 292.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
M. Kooijman, G. A. Rongen, P. Smits, and M. T.E. Hopman
Preserved {alpha}-Adrenergic Tone in the Leg Vascular Bed of Spinal Cord-Injured Individuals
Circulation, November 11, 2003; 108(19): 2361 - 2367.
[Abstract] [Full Text] [PDF]

Home page
 NeurologyHome page
C. H. Schick, K. Fronek, A. Held, F. Birklein, W. Hohenberger, and M. Schmelz
Differential effects of surgical sympathetic block on sudomotor and vasoconstrictor function
Neurology, June 10, 2003; 60(11): 1770 - 1776.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
G. Jacob, F. Costa, S. Vincent, D. Robertson, and I. Biaggioni
Neurovascular Dissociation With Paradoxical Forearm Vasodilation During Systemic Tyramine Administration
Circulation, May 20, 2003; 107(19): 2475 - 2479.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow All Versions of this Article:
92/5/2019    most recent
01025.2001v1
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (25)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Eisenach, J. H.
Right arrow Articles by Joyner, M. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Eisenach, J. H.
Right arrow Articles by Joyner, M. J.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online