Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system in which autoimmune mechanisms are relevant. In some patients with MS, signs of a vascular dysregulation can be observed (e.g., patients with MS show symptoms such as a tendency to cold extremities and migraine more often than healthy people) (1,2). This observation would be compatible with an increase of plasma ET-1. Furthermore, the possible involvement of vascular factors in the pathogenesis of the brain lesions or the symptoms has been discussed with controversy for decades (3,4).
The peptide endothelin-1 (ET-1), produced and released mostly but not exclusively by endothelial cells, is one of the most potent known physiologic vasoconstrictors. Because an increased plasma level of ET-1 could explain some of the vascular symptoms of patients with MS and because increased levels of endothelin were described in the cerebrospinal fluid of patients with MS (5), we tested the hypothesis that patients with MS have increased ET-1 plasma levels.
The ET-1 plasma levels of patients with clinically defined MS (6)(10 males, mean age 43.8 ± 14.7 years, range 21–68 years and 10 females, mean age 41.6 ± 11.5 years, range 23–56 years) have been compared with the levels of healthy volunteers (10 males, mean age 45 ± 14.1 years, range 27–69 years and 10 females, mean age 41.7 ± 11.1 years, range 23–55 years). All patients with systemic conditions known to be associated with increased ET-1 levels were excluded from the study (7). At the moment blood was taken, all patients were mobile and in a stable phase of their disease. None had experienced a clinical relapse for at least 3 months. No patient was on any systematic medication. Written informed consent was obtained from all patients. Blood samples were taken after 30 minutes of rest in a supine position at room temperature. ET-1 plasma levels were determined by specific radioimmunoassay, as previously described (8). All values are expressed as mean ± standard deviation (SD). The ET-1 level of patients with MS was compared to age-and sex-pair-matched healthy subjects with the help of a dependent t-test. The influence of stages and types of MS were tested with an analysis of variance. The correlation with age and duration of MS was done with a Pearson correlation. A p value less than 0.05 was considered to be significant.
Plasma ET-1 levels were markedly and significantly elevated, by 224%, in patients with MS (p < 0.005) and averaged 3.5 ± 0.83 pg/mL (min 2.13, max 5.37 pg/mL) compared to 1.56 ± 0.3 pg/mL (min 0.9, max 2.13 pg/mL) in age-and sex-matched healthy volunteers (Fig. 1).
Our study shows that patients with MS have markedly increased ET-1 plasma levels. No correlation to age could be found in healthy subjects or patients with MS. The different forms of MS and the different stages had no significant influence on the results. No correlation to the duration of the disease or to the mean Kurtzke Expanded Disability Status Scale (EDSS) could be found. An increased ET-1 plasma level in patients with MS goes with the finding of increased endothelin levels in the cerebrospinal fluid of patients with MS (5). Whether the increased ET-1 levels in patients with MS reflect an increased ET-1 production, a decreased metabolism, or a decreased excretion is not yet clear. An increase in ET-1 plasma level is not specific for MS. Similar plasma levels have been reported in patients with other autoimmune diseases, such as antiphospholipid syndrome, rheumatoid arthritis, and lupus erythematosus, and also in some infectious diseases, such as AIDS (7). Although increased endothelin levels were also found in the cerebrospinal fluid of patients with MS, the possible role of endothelin for neural transmission and regulation is not known and needs to be further investigated. In diabetic neuropathy, increased ET-1 activity exacerbates neural degeneration (reduction of nerve conduction velocity and endoneural blood flow) (9). In the case that ET-1 plays a role in the pathogenesis of MS, endothelin receptor blockers may offer some additional options.
The authors thank J. Boden, M. Joos, S. Lengen, and A. Zosso for expert technical assistance. This work was supported by the Swiss National Science Foundation (grant 32-49648.96).
1. Watkins S, Espir M. Migraine and multiple sclerosis. J Neurol Neurosurg Psych 1969; 32:35–7.
2. Freedman MS, Gray TA. Vascular headache: a presenting symptom of multiple sclerosis. Can J Neurol Sci 1989; 16:63–6.
3. Putnam TJ. The pathogenesis of multiple sclerosis: a possible vascular factor. N Engl J Med 1933; 209:786–90.
4. James PB. Multiple sclerosis or blood-brain barrier disease. Lancet 1989; 1:46.
5. Speciale L, Sarasella M, Ruzzante S, et al. Endothelin and nitric oxide levels in cerebrospinal fluid of patients with multiple sclerosis. J Neurovirol 2000; 6(suppl 2):S62–6.
6. Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983; 13:227–31.
7. Flammer J, Pache M, Resink T. Vasospasm, its role in the pathogenesis of diseases with particular reference to the eye. Prog Ret Eye Res
, in press.
8. Barton M, Shaw SG, d'Uscio L, et al. Angiotensin increases vascular and retinal endothelin-1 and functional endothelin converting enzyme activity in vivo: role of ETA receptors for endothelin regulation. Biochem Biophys Res Comm 1997; 238:861–5.
9. Cameron NE, Dines KC, Cotter MA. The potential contribution of endothelin-1 to neurovascular abnormalities in streptozoticin-diabetic rats. Diabetologia 1994; 37:1209–15.