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Increased endothelin-1 and diminished nitric oxide levels in blister fluids of patients with intermediate cold type complex regional pain syndrome type 1
BMC Musculoskeletal Disorders volume 7, Article number: 91 (2006)
In complex regional pain syndrome type 1 (CRPS1) pro-inflammatory mediators and vascular changes play an important role in the sustained development and outcome of the disease. The aim of this study was to determine the involvement of vasoactive substances endothelin-1 (ET-1) and nitric oxide (NO) during early chronic CRPS1.
Included were 29 patients with CRPS 1 who were diagnosed during the acute stage of their disease and observed during follow-up visits. Disease activity and impairment were determined and artificial suction blisters were made on the CRPS1 and the contralateral extremities for measurements of IL-6, TNF-α, ET-1 and nitrate/nitrite (NOx).
The levels of IL-6, TNF-α and ET-1 in blister fluid in the CRPS1 extremity versus the contralateral extremity were significantly increased and correlated with each other, whereas NOx levels were decreased.
The NOx/ET-1 ratio appears to be disturbed in the intermediate stage of CRPS, resulting in vasoconstriction and consequently in a diminished tissue blood distribution.
Complex regional pain syndrome (CRPS) is a painful disorder which mainly occurs as a complication after surgery or trauma, and the main characteristics are continuous pain, marked changes in tissue blood flow and skin surface temperature, oedema and sweating, movement disorders and trophic changes of the skin [1, 2]. The severity of the symptoms is disproportionate to the initial event. The diagnosis of CRPS is entirely based upon clinical criteria [3, 4]. In the Netherlands, the incidence of CRPS1 is approximately 2.6% for different fractures, which results in approximately 5100 new patients yearly, of whom a substantial part will not recover completely [5–7]. The female to male ratio is approximately 3:1, with a median age of 52.7 years at onset . The pathophysiology of CRPS1 is not unravelled yet, but growing evidence indicates the involvement of an exaggerated inflammatory processes. Both central and peripheral mechanisms have been proposed to play a prominent role. Central sensitization leading to exacerbation of pain is thought to result from neuroimmune activation of cells in the peripheral nervous system . During the neurogenic inflammation, neuropeptides  and cytokines and other mediators are released . This leads to a so-called 'warm dystrophy' with signs of inflammation such as redness, increased skin temperature, loss of function and pain [4, 5, 10].
During the chronic, disabling stage of the disease, in general the following changes occur: i) signs of extravasation, and oedema changes into atrophy, ii) regional blood flow declines, and iii) increased skin temperatures change into diminished temperatures. Permanent damage of nerve endings can lead to less endothelium-dependent vasodilation and result in a diminished regional blood distribution, the so-called 'cold dystrophy' [11, 12]. Both continuous pain and signs of 'cold dystrophy' can lead to assumed irreversible disuse. The contribution of endothelial derived factors could be crucial; endothelin-1 (ET-1) is a proven potent vasoconstrictive agent that is also believed to affect hyperalgesia , muscle weakness and movement disorders , and oedema .
In contrast to skeletal muscle resistance vessels, ET-1 contributes to the maintenance of skin microvascular tone through both ETA and ETB receptor-mediated vasoconstriction . The initially produced pro-inflammatory cytokines tumour necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) also play an important role in the initial and intermediate phases of the disease [9, 17]. TNF-α is known to decrease eNOS mRNA levels by increasing the rate of mRNA degradation [18, 19]. In the human forearm, TNF-α promotes ET-1 production . On the other hand, ET-1 also promotes TNF-α and IL-6 production in skin-derived mast cells , one of the cells which seem to play a prominent role in the acute phase of CRPS1 .
The present study aimed to investigate the involvement of the vasoactive substances ET-1 and nitric oxide (NO) in intermediate/cold type CRPS1 in relation to inflammatory mediators.
For this study 29 patients (6 males, 23 females; mean age 48 ± 11.3 (SD) years) with CRPS1 in one hand according to the criteria of Bruehl , were included. The patients had a mean duration of their disease of 2.8 ± 1.4 (SD) years, all being in the intermediate phase between the acute inflammatory stage and the early atrophic stage.
The mean disease activity of the patients was 35 on a scale of 0–100, calculated using the impairment sum score according to Oerlemans , representing a low to medium disease activity.
The Medical Ethics Committee of the Erasmus MC approved the study protocol (MEC 2004-159). The research was carried out in accordance with the Declaration of Helsinki (2000) of the World Medical Association and written informed consent was obtained from all participants.
2.2. Blister fluid collection
Artificial blisters were induced by means of a suction method [9, 17, 24–27]. A 3-hole (5 mm diameter per hole) skin suction chamber was positioned on the skin of the upper extremity, on the dorsal side of the involved hand and on the flexor side of the contralateral forearm. The latter site was used in all our previous studies to reduce the inconvenience for the patient and to enable a comparison between our studies [5, 9, 17, 22, 28, 29].
A vacuum of 300 mm Hg negative pressure was applied with an Atmoforte 350A aspirator pump (ATMOS Medizintechnik, Lenzkirch, Germany), which was reduced after 15 minutes to 250 mm Hg and again, 15 minutes later, reduced to 200 mm Hg. This negative pressure was maintained until blisters containing sufficient fluid had been developed, but not longer than 2.5 hours. The contents of the blisters were punctured and pooled from each side into a 1.5 ml Eppendorff conical polypropylene tube and centrifuged for 5 minutes at 1600 × g. The mean recovery of supernatants from control blisters was 144 ± 17 (± S.E.M.) μl fluid, and 106 ± 14 μl blister fluid from the CRPS1 side. All samples were stored in 1 ml conical polypropylene tubes at -80°C until analysis.
2.3. Measurements of cytokines
In order to determine the contribution of pro-inflammatory cytokines to the disease activity, both IL-6 and TNF-α were determined [9, 17]. Blister fluid samples were diluted 1:4 in appropriate calibrator diluent assay buffer for the direct measurement of cytokines. Cytokine assays were performed following the manufacturer's protocol (Pelikine™ human ELISA compact kits for IL-6 (cat. no. M1906) and TNF-α (cat. no. M1920), Sanquin, Amsterdam, The Netherlands). The standard curve ranges and mean calculated zero signal plus 3 SD for IL-6 were 0–450 pg/ml and 0.2 pg/ml, respectively; and for TNF-α 0–1000 pg/ml and 1 pg/ml, respectively. The requested solutions were provided with the ELISA compact kits and additional tool kits (Pelikine-Tool™ set (cat. no. M1980), Sanquin, Amsterdam, The Netherlands). Following the manufacturer's step-by-step instructions, at the end of the procedure the absorbance per well was measured at 450 nm with a Medgenix ELISA reader. Sample concentrations were calculated using the appropriate standard calibration lines and the Softmax® software of the reader.
2.4. Measurement of endothelin-1
ET-1 concentrations were determined in paired blister fluid samples which were available for 22 patients. Blister fluids were diluted 1:2 in appropriate diluent assay buffer. An ELISA-based commercial assay kit was purchased from R&D Systems (cat. no. QET00, Abingdon, UK). The QuantiGlo ET-1 chemiluminescent immunoassay is a solid phase ELISA designed to measure ET-1 levels in human fluids without extraction procedures. It contains synthetic human ET-1 and antibodies raised against the synthetic factor, which has been shown to accurately quantitate human ET-1. A microplate luminometer was used to measure the intensity of light emitted in RLUs (relative light units). The standard curve ranged from 0–1000 pg/ml. Raw data were transferred to a personal computer in which a log concentration-logit RLU equation was performed after which sample concentrations were calculated. The minimal detectable concentration was 0.16 pg/ml.
2.5. Measurement of nitric oxide
Sufficient remaining sample volume was available from 17 paired blister fluid samples to perform the assay procedure for the quantitative determination of nitrate and nitrite concentrations. Samples were diluted 1:1 in appropriate diluent assay buffer. A complete assay kit was obtained from R&D Systems (cat. no. DE1500, Abingdon, UK). This assay determines NO based on the enzymatic conversion of nitrate to nitrite by nitrate reductase. The reaction is followed by a colorimetric detection of nitrite as an azo dye product of the Griess reaction. At the end of procedure the chromophoric azo derivative which absorbs light at 540 nm is detected in a Medgenix ELISA reader, after which sample concentrations are calculated using the appropriate standard calibration line by means of the Softmax® software of the reader. The standard curve ranges for nitrite and nitrate were respectively 0–200 and 0–100 nmol/ml and the minimal detectable concentrations were respectively 0.22 and 0.54 nmol/ml. Sample concentrations were expressed as total NOx in nmol/ml.
2.6. Statistical analysis
The Wilcoxon signed ranks test was used for comparisons between measurements in blister fluid obtained from the CRPS1 and the contralateral extremity. Correlation coefficients between different parameters were determined by the Spearman's test for untransformed data. SPSS (version 14) for Windows was used and the significance level was set at p < 0.05.
Pro-inflammatory cytokines IL-6 and TNF-α and vasoactive ET-1 and NOx were determined in blister fluid obtained from the involved CRPS1 limb and the contra-lateral limb.
In Figures 1 and 2 the distributions of blister concentrations have been plotted as a correlation between CRPS1 samples (Y-axis) and contralateral samples (X-axis). Successively (Fig. 1a) IL-6, (Fig. 1b) TNF-α, (Fig. 2a) ET-1 and (Fig. 2b) NOx are displayed. In each plot the straight line indicates per definition a CRPS to contralateral ratio of 1.00 in case no difference was observed. Both in the IL-6, TNF-α and ET-1 distribution plots, the main number of data-points are located in the upper-left triangle, indicating a CRPS to contralateral ratio above 1.00. On the contrary, in the NOx distribution plot, the main number of data points are located in the lower-right triangle, indicating a CRPS to contralateral ratio less than 1.00.
The Wilcoxon signed ranks test was used to assign differences in paired samples (blister fluid obtained from the CRPS1 and the contralateral extremity in the same patient).
Increments in the paired sample tests of IL-6, TNF-α and ET-1 were significant (p-values of 0.001, 0.003 and 0.002, respectively), whereas NOx in paired samples was significantly decreased (p-value 0.044).
Spearman's correlation coefficients between blister fluid parameters were determined. Significant correlations between IL-6, TNF-α and ET-1 were found (0.79, 0.44 and 0.67 for IL-6/TNF-α, IL-6/ET-1 and TNF-α/ET-1, respectively and p-values of p < 0.001, p = 0.039 and p = 0.001, respectively).
This is the first study to investigate levels of ET-1 and NOx in blister fluids obtained from CRPS1-involved extremities. Apart from a study comparing ET-1 with disease severity in the skin of psoriatic patients , only Eisenberg et al. have investigated the possible contribution of ET-1 in CRPS . In that study, ET-1 concentrations were determined in venous plasma from the contralateral limb of CRPS1 patients and did not differ significantly from values found in patients with other painful conditions and in healthy controls. The ET-1 levels found in controls and patients (mean 2.7 and 3.2 pg/ml) were, however, much higher than those reported in the literature [32, 33]. Eisenberg et al. concluded that ET-1 in plasma can not be regarded as a laboratory marker for CRPS. The mean disease duration of their CRPS patients was 2 years, with a study population of relatively young patients (mean 30 years) and a male/female ratio of 2/1 . These characteristics were not comparable with our study, in which age, duration of CRPS1 and the male/female ratio were much more comparable with demographic characteristics commonly found in the literature. In general, the main peak in the development of CRPS is seen at the age of 52 years and the male/female ratio is between 1:3 and 1:4.
Kuryliszyn-Moskal et al. found synovial ET-1 levels of 15.5 pg/ml  and similar serum levels . Although the ET-1 levels we found in blister fluid (3.2 pg/ml) might be diminished due to interstitial dilution, we believe that interstitial levels better reflect local processes in CRPS1 than plasma measurements. This is confirmed by the finding of high ET-1 concentrations in blister fluids at wound regions of burn patients .
The role of NO in CRPS has not yet been investigated, although increased NO production from interferon-γ stimulated peripheral blood monocytes obtained from CRPS patients has been observed, in patients with apparently active disease . We found an inverse relationship between ET-1 and NOx in blister samples. This has also been observed in vascular homeostasis where endothelium dysfunction plays a prominent role . In venous plasma of patients with erectile dysfunction, significantly increased ET-1 and decreased NO levels were found . In pathological situations circulating pro-inflammatory cytokines induce the expression of iNOS and ET-1 in smooth muscle cells, also downregulating endothelial eNOS expression, resulting in an elevated ET-1 production and a decrease of NO [18, 39]. This was observed in our study: a significant increase of IL-6 and TNF-α, which causes a marked increase of ET-1 and a slight but significant decrease of NOx. These results confirm the findings of Munnikes et al. who studied patients with an intermediate duration of CRPS (median 20 months) and also found a significant elevation of IL-6 and TNF-α in the involved extremity compared with the uninvolved extremity . That group consisted of 25 patients who had significantly improved on volume difference, AROM, VAS and McGill Pain Questionnaire, which makes their group comparable to our patients with a Impairment Sum Score  of 35. Thus there is increasing evidence for the role of proinflammatory cytokines in the initiation and development of CRPS. A longitudinal study is needed that follows selected CRPS patients from the acute to the chronic stage to determine the precise involvement of inflammatory cytokines in the disease activity.
Disuse during chronic CRPS is a common phenomenon. Vasoconstriction is usually followed by local reductions in blood flow [11, 12]. It is unclear what the effect of disuse on the production of ET-1 and NO could be, but the plasma NOx concentration in healthy young humans significantly increases after exercise, with a significant decrease of ET-1 . In healthy subjects, the physiological role of ET-1 in nonworking muscles during exercise has been described . In healthy women, the ET-1 plasma concentration increases with age, which could be significantly counteracted after exercise . Animal studies have shown that endogenous ET-1 participates in the sustained development of the disease in the redistribution of tissue blood flow .
In a previous study we observed that treatment with anti-TNF-α initiates recovery during the inflammatory stage of CRPS1 . The effect of this intervention on the release of ET-1 and NOx is still unclear. Assuming a diminished blood flow, inhibition of the NO synthase is not advisable; on the contrary, NO donors should be supplemented . Besides the smooth muscle constrictive effects of ET-1, hyperalgesia and pain could also be the result of ET receptor stimulation. Therefore, specific ETA receptor antagonists (such as atrasentan) could provide remission . In pulmonary arterial hypertension, after treatment with the ET receptor antagonist bosentan, the suppression of NO synthesis was abolished and reversed to normal values of controls .
During the acute stage of CRPS1 large amounts of NO will be formed through activation of the inducible NO synthetase (iNOS). In that stage, the blood distribution has been increased which causes an increase of local skin temperature. In the endothelial cell NO will be formed from L-arginine through eNOS activation. Formation of NO could also occur after receptor stimulated activation of constitutive NOS (cNOS) or activation of neuronal NOS (nNOS) in nerve endings. In all cases this will result in increased vasodilation . TNF-α counteracts the activation of eNOS , whereas induction of iNOS in smooth muscle cells will be stimulated to generate NO . In the trophic phase of CRPS1 there will be a decline in the contribution of inflammatory mediators. Consequently, in combination with disuse of the extremity, less NO could be generated, resulting in diminished basal relaxation and retarded blood distribution, after which signs of the 'cold dystrophy' will become apparent.
In the vascular system a clear crosstalk exists between the NO and the ET-1 system. It seems that this interrelationship also exists in CRPS. It is obvious that NO functions as a controlling mechanism against ET-1-induced vasoconstriction. The stage of the disease, the acute or inflammatory phase, or the chronic and/or trophic phase, determines the involvement of inflammatory cytokines which could promote ET-1 production, leading to vasoconstriction and consequently to a diminished tissue blood distribution. A longitudinal study following CRPS patients during the course of the disease is needed to investigate the NOx/ET-1 ratio as an indicator of vascular involvement.
Complex Regional Pain Syndrome
- eNOS iNOS:
nNOS constitutive and neuronal Nitric Oxide Synthetase
Nitrite and Nitrate
- ETA :
Endothelin type A
- ETB :
Endothelin type B
Tumour Necrosis Factor alpha
messenger Ribo Nucleid Acid
Relative Light Unit
Reflex Sympathetic Dystrophy Syndrome Association
Trauma Related Neuronal Dysfunction
Janig W, Baron R: Complex regional pain syndrome: mystery explained?. Lancet Neurol. 2003, 2 (11): 687-697. 10.1016/S1474-4422(03)00557-X.
Baron R, Janig W: Complex regional pain syndromes--how do we escape the diagnostic trap?. Lancet. 2004, 364 (9447): 1739-1741. 10.1016/S0140-6736(04)17416-3.
Bruehl S, Harden RN, Galer BS, Saltz S, Bertram M, Backonja M, Gayles R, Rudin N, Bhugra MK, Stanton-Hicks M: External validation of IASP diagnostic criteria for Complex Regional Pain Syndrome and proposed research diagnostic criteria. International Association for the Study of Pain. Pain. 1999, 81 (1-2): 147-154. 10.1016/S0304-3959(99)00011-1.
Bruehl S, Harden RN, Galer BS, Saltz S, Backonja M, Stanton-Hicks M: Complex regional pain syndrome: are there distinct subtypes and sequential stages of the syndrome?. Pain. 2002, 95 (1-2): 119-124. 10.1016/S0304-3959(01)00387-6.
Huygen FJ, de Bruijn AG, Klein J, Zijlstra FJ: Neuroimmune alterations in the complex regional pain syndrome. Eur J Pharmacol. 2001, 429 (1-3): 101-113. 10.1016/S0014-2999(01)01310-3.
Dijkstra PU, Groothoff JW, ten Duis HJ, Geertzen JH: Incidence of complex regional pain syndrome type I after fractures of the distal radius. Eur J Pain. 2003, 7 (5): 457-462. 10.1016/S1090-3801(03)00015-6.
Mos M, Bruijn AGJ, Huygen FJPM, Dieleman JP, Stricker BHC, Sturkenboom MCJM: The incidence of Complex Regional Pain Syndrome: a population-based study. Submitted. 2006
Birklein F: Complex regional pain syndrome. J Neurol. 2005, 252 (2): 131-138. 10.1007/s00415-005-0737-8.
Huygen FJ, De Bruijn AG, De Bruin MT, Groeneweg JG, Klein J, Zijlstra FJ: Evidence for local inflammation in complex regional pain syndrome type 1. Mediators Inflamm. 2002, 11 (1): 47-51. 10.1080/09629350210307.
Schwartzman RJ, Popescu A: Reflex sympathetic dystrophy. Curr Rheumatol Rep. 2002, 4 (2): 165-169.
Wasner G, Heckmann K, Maier C, Baron R: Vascular abnormalities in acute reflex sympathetic dystrophy (CRPS I): complete inhibition of sympathetic nerve activity with recovery. Arch Neurol. 1999, 56 (5): 613-620. 10.1001/archneur.56.5.613.
Wasner G, Schattschneider J, Heckmann K, Maier C, Baron R: Vascular abnormalities in reflex sympathetic dystrophy (CRPS I): mechanisms and diagnostic value. Brain. 2001, 124 (Pt 3): 587-599. 10.1093/brain/124.3.587.
Baamonde A, Lastra A, Villazon M, Bordallo J, Hidalgo A, Menendez L: Involvement of endogenous endothelins in thermal and mechanical inflammatory hyperalgesia in mice. Naunyn Schmiedebergs Arch Pharmacol. 2004, 369 (2): 245-251. 10.1007/s00210-003-0841-1.
Dahlof B, Gustafsson D, Hedner T, Jern S, Hansson L: Regional haemodynamic effects of endothelin-1 in rat and man: unexpected adverse reaction. J Hypertens. 1990, 8 (9): 811-817. 10.1097/00004872-199009000-00004.
Oda M, Yokomori H, Han JY: Regulatory mechanisms of hepatic microcirculation. Clin Hemorheol Microcirc. 2003, 29 (3-4): 167-182.
Leslie SJ, Rahman MQ, Denvir MA, Newby DE, Webb DJ: Endothelins and their inhibition in the human skin microcirculation: ET[1-31], a new vasoconstrictor peptide. Br J Clin Pharmacol. 2004, 57 (6): 720-725. 10.1111/j.1365-2125.2004.02074.x.
Huygen FJ, Niehof S, Zijlstra FJ, van Hagen PM, van Daele PL: Successful treatment of CRPS 1 with anti-TNF. J Pain Symptom Manage. 2004, 27 (2): 101-103. 10.1016/j.jpainsymman.2003.12.006.
Alonso D, Radomski MW: The nitric oxide-endothelin-1 connection. Heart Fail Rev. 2003, 8 (1): 107-115. 10.1023/A:1022155206928.
Yoshizumi M, Perrella MA, Burnett JC, Lee ME: Tumor necrosis factor downregulates an endothelial nitric oxide synthase mRNA by shortening its half-life. Circ Res. 1993, 73 (1): 205-209.
Patel JN, Jager A, Schalkwijk C, Corder R, Douthwaite JA, Yudkin JS, Coppack SW, Stehouwer CD: Effects of tumour necrosis factor-alpha in the human forearm: blood flow and endothelin-1 release. Clin Sci (Lond). 2002, 103 (4): 409-415.
Matsushima H, Yamada N, Matsue H, Shimada S: The effects of endothelin-1 on degranulation, cytokine, and growth factor production by skin-derived mast cells. Eur J Immunol. 2004, 34 (7): 1910-1919. 10.1002/eji.200424912.
Huygen FJ, Ramdhani N, Van Toorenenbergen A, Klein J, Zijlstra FJ: Mast cells are involved in inflammatory reactions during Complex Regional Pain Syndrome type 1. Immunol Lett. 2004, 91 (2-3): 147-154. 10.1016/j.imlet.2003.11.013.
Oerlemans HM, Oostendorp RA, de Boo T, van der Laan L, Severens JL, Goris JA: Adjuvant physical therapy versus occupational therapy in patients with reflex sympathetic dystrophy/complex regional pain syndrome type I. Arch Phys Med Rehabil. 2000, 81 (1): 49-56. 10.1053/apmr.2000.0810049.
Prens EP, Benne K, van Damme J, Bakkus M, Brakel K, Benner R, van Joost T: Interleukin-1 and interleukin-6 in psoriasis. J Invest Dermatol. 1990, 95 (6 Suppl): 121S-124S. 10.1111/1523-1747.ep12874991.
Macdonald N, Cumberbatch M, Singh M, Moggs JG, Orphanides G, Dearman RJ, Griffiths CE, Kimber I: Proteomic analysis of suction blister fluid isolated from human skin. Clin Exp Dermatol. 2006, 31 (3): 445-448. 10.1111/j.1365-2230.2006.02078.x.
Michiels JJ, Zijlstra FJ: Prostaglandin cyclooxygenase products but not thromboxane A2 are involved in the pathogenesis of erythromelalgia in thrombocythaemia. Mediators Inflamm. 1993, 2: 385 -3389.
Reilly DM, Green MR: Eicosanoid and cytokine levels in acute skin irritation in response to tape stripping and capsaicin. Acta Derm Venereol. 1999, 79 (3): 187-190. 10.1080/000155599750010931.
Heijmans-Antonissen C, Wesseldijk F, Munnikes RJ, Huygen FJ, van der Meijden P, Hop WC, Hooijkaas H, Zijlstra FJ: Multiplex bead array assay for detection of 25 soluble cytokines in blister fluid of patients with complex regional pain syndrome type 1. Mediators Inflamm. 2006, 2006 (1): 28398-
Munnikes RJ, Muis C, Boersma M, Heijmans-Antonissen C, Zijlstra FJ, Huygen FJ: Intermediate stage complex regional pain syndrome type 1 is unrelated to proinflammatory cytokines. Mediators Inflamm. 2005, 2005 (6): 366-372. 10.1155/MI.2005.366.
Bonifati C, Mussi A, Carducci M, Pittarello A, D'Auria L, Venuti A, Bagnato A, Salani D, Fazio M, Ameglio F: Endothelin-1 levels are increased in sera and lesional skin extracts of psoriatic patients and correlate with disease severity. Acta Derm Venerol. 1998, 78 (1): 22-26. 10.1080/00015559850135779.
Eisenberg E, Erlich T, Zinder O, Lichinsky S, Diamond E, Pud D, Davar G: Plasma endothelin-1 levels in patients with complex regional pain syndrome. Eur J Pain. 2004, 8 (6): 533-538. 10.1016/j.ejpain.2003.12.003.
El Melegy NT, Ali ME, Awad EM: Plasma levels of endothelin-1, angiotensin II, nitric oxide and prostaglandin E in the venous and cavernosal blood of patients with erectile dysfunction. BJU Int. 2005, 96 (7): 1079-1086. 10.1111/j.1464-410X.2005.05780.x.
Pache M, Schwarz HA, Kaiser HJ, Wuest P, Kloti M, Dubler B, Flammer J: Elevated plasma endothelin-1 levels and vascular dysregulation in patients with rheumatoid arthritis. Med Sci Monit. 2002, 8 (9): 616-619.
Haq A, El-Ramahi K, Al-Dalaan A, Al-Sedairy ST: Serum and synovial fluid concentrations of endothelin-1 in patients with rheumatoid arthritis. J Med. 1999, 30 (1-2): 51-60.
Kuryliszyn-Moskal A, Klimiuk PA, Sierakowski S, Ciolkiewicz M: A study on vascular endothelial growth factor and endothelin-1 in patients with extra-articular involvement of rheumatoid arthritis. Clin Rheumatol. 2005, 1-6.
Wakisaka N, Kubota T, Ando K, Aihara M, Inoue H, Ishida H: Endothelin-1 kinetics in plasma, urine, and blister fluid in burn patients. Ann Plast Surg. 1996, 37 (3): 305-309. 10.1097/00000637-199609000-00012.
Hartrick CT: Increased production of nitric oxide stimulated by interferon-gamma from peripheral blood monocytes in patients with complex regional pain syndrome. Neurosci Lett. 2002, 323 (1): 75-77. 10.1016/S0304-3940(02)00112-X.
Alonso D, Radomski MW: Nitric oxide, platelet function, myocardial infarction and reperfusion therapies. Heart Fail Rev. 2003, 8 (1): 47-54. 10.1023/A:1022194921040.
Erkan E, Devarajan P, Kaskel F: Role of nitric oxide, endothelin-1, and inflammatory cytokines in blood pressure regulation in hemodialysis patients. Am J Kidney Dis. 2002, 40 (1): 76-81. 10.1053/ajkd.2002.33915.
Oerlemans HM, Goris RJ, Oostendorp RA: Impairment level sumscore in reflex sympathetic dystrophy of one upper extremity. Arch Phys Med Rehabil. 1998, 79 (8): 979-990. 10.1016/S0003-9993(98)90098-3.
Maeda S, Miyauchi T, Kakiyama T, Sugawara J, Iemitsu M, Irukayama-Tomobe Y, Murakami H, Kumagai Y, Kuno S, Matsuda M: Effects of exercise training of 8 weeks and detraining on plasma levels of endothelium-derived factors, endothelin-1 and nitric oxide, in healthy young humans. Life Sci. 2001, 69 (9): 1005-1016. 10.1016/S0024-3205(01)01192-4.
Tanabe K, Yamamoto A, Suzuki N, Yokoyama Y, Osada N, Nakayama M, Akashi Y, Seki A, Samejima H, Oya M, Murabayashi T, Omiya K, Itoh H, Miyake F, Murayama M: Physiological role of endothelin-1 in nonworking muscles during exercise in healthy subjects. Jpn Circ J. 2000, 64 (1): 27-31. 10.1253/jcj.64.27.
Maeda S, Tanabe T, Miyauchi T, Otsuki T, Sugawara J, Iemitsu M, Kuno S, Ajisaka R, Yamaguchi I, Matsuda M: Aerobic exercise training reduces plasma endothelin-1 concentration in older women. J Appl Physiol. 2003, 95 (1): 336-341.
Maeda S, Miyauchi T, Iemitsu M, Tanabe T, Irukayama-Tomobe Y, Goto K, Yamaguchi I, Matsuda M: Involvement of endogenous endothelin-1 in exercise-induced redistribution of tissue blood flow: an endothelin receptor antagonist reduces the redistribution. Circulation. 2002, 106 (17): 2188-2193. 10.1161/01.CIR.0000038362.16740.A2.
Malmstrom RE, Weitzberg E: Endothelin and nitric oxide in inflammation: could there be a need for endothelin blocking anti-inflammatory drugs?. J Hypertens. 2004, 22 (1): 27-29. 10.1097/00004872-200401000-00006.
Nelson JB: Endothelin receptor antagonists. World J Urol. 2005, 23: 19 -127. 10.1007/s00345-004-0478-9.
Girgis RE, Champion HC, Diette GB, Johns RA, Permutt S, Sylvester JT: Decreased exhaled nitric oxide in pulmonary arterial hypertension: response to bosentan therapy. Am J Respir Crit Care Med. 2005, 172 (3): 352-357. 10.1164/rccm.200412-1684OC.
Meurs H, Maarsingh H, Zaagsma J: Arginase and asthma: novel insights into nitric oxide homeostasis and airway hyperresponsiveness. Trends Pharmacol Sci. 2003, 24 (9): 450-455. 10.1016/S0165-6147(03)00227-X.
The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2474/7/91/prepub
This study was funded by the Reflex Sympathetic Dystrophy Syndrome Association (RSDSA, USA) and performed within TREND (Trauma Related Neuronal Dysfunction), a knowledge consortium that integrates research on Complex Regional Pain Syndrome type 1. The project is supported by a Dutch government grant (BSIK03016).
The skilful help of Christel Muis and Martine Boersma (medical students), and Liesbeth Lagendijk (research nurse) was highly appreciated. The authors thank professor Arnold G. Vulto (Dept. of Hospital Pharmacy) for technical support, Dr. Dirk Stronks (Pain Expertise Center Rotterdam) for the statistical advise, Dr. Ilse Beckmann (Dept. of Obstetrics and Gynecology) and Dr. Frans Boomsma (Dept. of Internal Medicine) for the use of laboratory facilities, and Laraine Visser-Isles (Dept. of Anesthesiology) for editorial assistance.
The author(s) declare that they have no competing interests.
JGG carried out the measurements, was responsible for the coordination of the study and wrote the final version of the manuscript. FJPMH participated in the design of the study, performed the patient selection and revised the definitive article. CHA carried out the immunoassays and assisted in writing. SN participated in the measurements the statistical analysis and corrected the final document. FJZ was responsible for the design of the study, wrote the first draft of the manuscript, performed the statistical analysis and supervised the writing process. All authors read and approved the final manuscript.
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Groeneweg, J.G., Huygen, F.J., Heijmans-Antonissen, C. et al. Increased endothelin-1 and diminished nitric oxide levels in blister fluids of patients with intermediate cold type complex regional pain syndrome type 1. BMC Musculoskelet Disord 7, 91 (2006) doi:10.1186/1471-2474-7-91
- Nitric Oxide
- Complex Regional Pain Syndrome
- Blister Fluid
- Complex Regional Pain Syndrome Patient