No arguments for increased endothelial nitric oxide synthase activity in migraine based on peripheral biomarkers.
OBJECTIVE
To assess whether migraine patients display a chronic nitric oxide synthase (NOS) hyperactivity by comparing the nitric oxide (NO) production before and following a loading dose of L-arginine between migraine patients (interictally) and matched healthy control subjects. In addition, we evaluated whether a loading dose of L-arginine triggers an acute migraine headache in migraineurs.


METHODS
Twenty healthy subjects and 20 migraine patients participated in a 2-period, randomised, double-blind, placebo-controlled study. Each subject received a 30-min infusion, by peripheral vein, of 30 g L-arginine hydrochloride or placebo (i.e. an equal volume of 0.9% saline solution). Meanwhile, biomarkers associated with the L-arginine-NO pathway (i.e. exhaled NO/nasal NO), plasma citrulline and urinary excretion of nitrite/nitrate and cGMP were assessed before and for 6 h following the start of the infusion.


RESULTS
At baseline, exhaled NO and nasal NO were higher in migraineurs compared to healthy subjects (mean±95% confidence interval): 15.9 (8.8, 23.0) parts per billion (ppb) versus 10.8 (7.0, 14.5) ppb for exhaled NO (P=0.04) and 76.3 (61.2, 91.4) versus 61.6 (51.2, 72.0) ppb for nasal NO (P=0.03), respectively. The AUC0-6 in ppb for exhaled NO and nasal NO following L-arginine or saline infusion did not differ between both groups. The increase in L-citrulline, following L-arginine infusion, was smaller in migraine patients (15 (13, 18) µmol/l) compared to healthy volunteers (19 (16, 23) µmol/l; P=0.046). In healthy subjects, both nitrate and cGMP excretion were higher following L-arginine compared to placebo infusion: 132.63 (100.24, 165.02) versus 92.07 (66.33, 117.82) µmol/mmol creatinine for nitrate (P=0.014) and 50.53 (42.19, 58.87) versus 39.64 (33.94, 45.34) nmol/mmol creatinine for cGMP (P=0.0003), respectively. In migraineurs, excretion of these biomarkers was comparable following L-arginine or saline infusion.


CONCLUSIONS
The results of the present study do not support the idea of a generalised increase in NO synthase activity in migraine patients outside of a migraine attack. The smaller increase in plasma L-citrulline, urinary nitrate and cGMP excretion following L-arginine infusion in migraine patients might indicate dysfunction of endothelial NO synthase.
Center for Clinical Pharmacology, University Hospital Gasthuisberg (K U Leuven), Leuven, Belgium. bart.vanderschueren@uz.kuleuven.be
Bart J
BJ
Van der Schueren
Frederik H
FH
Verbrugge
René
R
Verbesselt
Anne
A
Van Hecken
Marleen
M
Depré
Jan N
JN
de Hoon
D019540:Area Under Curve; D001120:Arginine / Q000009:adverse effects / Q000378:metabolism*; D015415:Biomarkers / Q000032:analysis*; D002956:Citrulline / Q000097:blood; D006152:Cyclic GMP / Q000652:urine; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008881:Migraine Disorders / Q000201:enzymology*; D009566:Nitrates / Q000652:urine; D009569:Nitric Oxide / Q000032:analysis / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D009573:Nitrites / Q000652:urine
D015415:Biomarkers; D009566:Nitrates; D009573:Nitrites; D002956:Citrulline; D009569:Nitric Oxide; D001120:Arginine; D052250:Nitric Oxide Synthase Type III; D006152:Cyclic GMP