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Phil B.FontanarosaMD, Deputy EditorIndividualAuthorStephen J.LurieMD, PhD, Contributing EditorIndividualAuthor
To the Editor: Nitric oxide–mediated
damage has been implicated in a number of neurological diseases including
stroke1,2 and multiple
sclerosis (MS).3 For instance, monocytes
expressing high levels of nitric oxide synthetase have been found in plaques
from the brains of patients with MS.4 The
proximal agent of neuronal cell damage may be peroxynitrite, which is formed
in vivo from the synthesis of nitric oxide and superoxide.
Uric acid is a known peroxynitrite scavenger, and several lines of evidence
suggest that high serum levels of uric acid may offer protection against development
of MS. For instance, a survey of 20 million patient records revealed that
MS and gout were mutually exclusive diagnoses.4
In a murine model of MS, administration of uric acid was found to have a linear
dose-response protective effect, and patients with MS have lower levels of
uric acid than controls.4,5
To further assess this possible inverse relationship between nitric oxide
and uric acid, we performed a circadian analysis of these 2 substances in
a series of subjects without a history of either MS or gout.
In 1979, 11 healthy male volunteers, then aged 32 to 57 years, were
selected from a military reserve unit on the basis of good venous access.
In 1979, and again in 1988, 1993, and 1998, blood was obtained at 3-hour intervals
over a 24-hour period, and the uric acid concentration of each sample was
measured. Nitric oxide levels were also measured in the 1998 samples. Five
of the subjects developed type 2 diabetes during the study period, but no
other chronic diseases were reported. Data were analyzed for circadian characteristics
by population multicomponent analysis.6
The mean uric acid levels at the 4 successive measurement years were
0.40 mmol/L (95% confidence interval [CI], 0.33-0.46 mmol/L), 0.40 mmol/L
(95% CI, 0.36-0.43 mmol/L), 0.39 mmol/L (95% CI, 0.33-0.45 mmol/L), and 0.38
mmol/L (95% CI, 0.35-0.42 mmol/L), respectively. This stability of uric acid
over time allowed us to pool the values for the analysis. A significant circadian
rhythm was obtained for a harmonic model with 2 components (with periods of
24 hours and 8 hours) for both uric acid (P<.001)
and nitric oxide (P=.004). The timing of uric acid
peak and nitric oxide trough concentrations is virtually cosynchronous, at
5:08 and 5:32, respectively (Figure 1).
P values were calculated from testing the
0 amplitude assumption. MESOR indicates the midline estimating statistic of
rhythm; CI, confidence interval; amplitude, half the distance between the
maximum and minimum of the fitted curve; orthophase, lag from a defined reference
point of the crest time in the curve fitted to the data; and bathyphase, lag
from the same reference point of the time of lowest value in the curve fitted
to the data. The curve represented for each variable corresponds to the best
fitted model obtained by population multiple-components analysis (with corresponding
characteristics given in the table above). The arrows from the upper horizontal
axis indicate the circadian orthophase for each variable. The shaded area
on the timeline represents sleep.
The temporally reciprocal relationship between uric acid and nitric
oxide in these men suggests that their concentrations are physiologically
related. This observation supports previous results of the protective effects
of uric acid in nitric oxide–mediated diseases, such as MS.
Kanabrocki EL, Third JLHC, Ryan MD, et al. Circadian Relationship of Serum Uric Acid and Nitric Oxide. JAMA. 2000;283(17):2240–2241. doi:10.1001/jama.283.17.2235
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