Increased urinary nitric oxide metabolites in patients with multiple sclerosis correlates with early and relapsing disease

Nitric oxide ((NO)-N-.) has been implicated in the immunopathogenesis of MS as a potential mediator of neuronal loss. To investigate the role of (NO)-N-. in the development of progressive disease we measured the (NO)-N-. metabolites (nitrate and nitrite) and neopterin, in the urine of 129 patients with demyelinating disease (DD): 23 with clinically isolated syndromes compatible with demyelination and in 46 relapsing remitting (RR) and 60 patients with progressive MS. Eighty-nine of these 129 patients underwent Gd-enhanced MRI. In addition 58 normal control subjects (NC), 19 AIDS and 35 rheumatoid arthritis (RA) patients were studied. Patients with DD, AIDS and RA had significantly elevated urinary nitrate plus nitrite (nit:creat(urine)) and neopterin (neopt:creat(urine)) to creatinine ratios compared to NC subjects. (Median([25th-75th%]) nit:creat(urine): NC= 1183([962-1365]) vs DD=1245([875-2403]), AIDS=1686([1231-2531]), and RA=1950([1214-2726]) mu mol/mol, P<0.001 and median([25th-75th%]) neopt:creat(urine): NC=99([76-151]) vs DD=163([119-266]) AIDS=972([653-1456]), and RA=389([257-623]) mu mol/mol, P<0.001). Patients with early DD and RR MS had significantly elevated nit:creat(urine) compared to patients with Progressive MS (nit:creat(urine): 1612([1020-2733]) vs 1159([790-1641]) mu mol/mol, P=0.006). The nit:creat(urine) and nit:creat(urine) did not correlate with clinical relapse or MRI activity. Excretion of (NO)-N-. metabolites is increased in patients with early or relapsing-remitting disease. (NO)-N-. appears to be a double-edged sword, mediating tissue damage and modulating complex immunological functions which may be protective in MS.