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 μg/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.
Nitric oxide-induced headache in patients with chronic tension-type headache