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May 3, 2000

Circadian Relationship of Serum Uric Acid and Nitric Oxide

Author Affiliations

Phil B.FontanarosaMD, Deputy EditorIndividualAuthorStephen J.LurieMD, PhD, Contributing EditorIndividualAuthor

JAMA. 2000;283(17):2240-2241. doi:10.1001/jama.283.17.2235

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).

Figure. Comparison of Circadian Variation in Serum Nitric Oxide and Uric Acid
Figure. Comparison of Circadian Variation
in Serum Nitric Oxide and Uric Acid

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.

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