Experimental studies in humans have shown that
nitric oxide (NO) may play an important role in initiation of primary
headaches. It has been proposed that activation of
L-arginine-NO pathway and increased endogenous production of NO may be responsible for NO induced
headache. NO is synthesized from
L-arginine and that reaction also yields
citrulline. In the present study we aimed to investigate plasma levels of
citrulline and
arginine as markers of NO production after infusion of the NO donor,
glyceryl trinitrate (GTN). We recruited 16 patients with chronic
tension-type headache and 16 healthy controls. The subjects were randomly allocated to receive 0.5 microg/kg/min GTN or placebo over 20 min. Patients were examined on
headache free days. Blood samples were collected at baseline and 60 min after start of infusion. Both patients and controls developed stronger immediate
headache on the GTN day than on the placebo day (P = 0.008). The
headache was more pronounced in patients than in controls (P = 0.02). Plasma levels of
citrulline increased significantly 60 min after start of GTN infusion compared to placebo infusion in patients (P = 0.01) but not in controls (P = 0.50). Plasma levels of
arginine were unchanged in both patients (P = 0.12) and controls (P = 0.18). We suggest that GTN administration may trigger endogenous production of NO in patients with chronic
tension-type headache resulting in activation of perivascular sensory afferents.