Glutamine and citrulline concentrations reflect nitric oxide synthesis in the human nervous system

Although citrulline is produced by nitric oxide (NO) synthase upon activation of the NMDA glutamate receptor, nitrite and nitrate (NO_x) concentration is considered the best marker of NO synthesis, as citrulline is also metabolised by other enzymes. This study analyses the correlation between human cerebrospinal fluid NO_x and citrulline concentrations in order to determine the extent to which citrulline reflects NO synthesis and glutamatergic neurotransmission.

Participants were patients with acute neurological diseases undergoing lumbar puncture (n=240). NO_x and amino acid concentrations were determined by HPLC.

NO_x concentrations did not vary significantly where infection (p=0,110) or inflammation (p=0,349) were present. Multiple regression analysis showed that NO_x concentration was correlated with glutamine (r=-0,319, p<0,001) and citrulline concentrations (r=0,293, p=0,005) but not with the citrulline/arginine ratio (r=-0,160, p=0,173). ANCOVA confirmed that NO_x concentration was correlated with citrulline concentration (F=7,6, p=0,007) but not with the citrulline/arginine ratio (F=2,2, p=0,136), or presence of infection (F=1,8, p=0,173) or inflammation (F=1,4, p=0,227). No association was found between NO_x and arginine or glutamate concentrations.

The results suggest that CSF citrulline concentration reflects NO_x synthesis to some extent, despite the contribution of other metabolic pathways. In addition, this study shows that glutamine is an important modulator of NO synthase activity, and that arginine and glutamate are not correlated with NO_x.