Effects of sumatriptan on nitric oxide and superoxide balance during glyceryl trinitrate infusion in the rat. Implications for antimigraine mechanisms.
Infusion of glyceryl trinitrate (GTN) into patients with migraine precipitates the onset of a migraine attack several hours after completion of the infusion. Using an infusion of GTN into anaesthetised rats, this study investigates the relationship of regional cerebral blood flux rCBF(ldf), cortical nitric oxide (NO) and cortical superoxide concentrations and the effect of sumatriptan on each variable. In saline treated animals, a 30 min infusion of GTN (2 microgram kg(-1) min(-1), i.v.) was found to markedly increase cortical rCBF(ldf) (133+/-3% of baseline) and NO concentrations (141+/-13% of baseline). Superoxide levels exhibited an inverse relationship to NO levels, decreasing below basal to 48+/-14% of baseline. It is hypothesised that high NO levels during GTN infusion may decrease the detectable superoxide due to "leeching" of the superoxide into low level peroxynitrite formation. In the presence of sumatriptan, a decrease below baseline in cortical rCBF(ldf) (82+/-5% of baseline) and NO concentration (64+/-13% of baseline) was observed throughout GTN infusion, although superoxide levels significantly increased above baseline by 105+/-14 nM (p<0.05, ANOVA post hoc LSD test). The mechanism for this action of sumatriptan is unknown but may include; modulation of cell redox state, NO scavenging or direct manipulation of superoxide release.
Read
S J
SJ
Neuroscience Research, Smithkline Beecham Pharmaceuticals, New Frontiers Science Park, Third Avenue, Harlow, UK.
Manning
P
P
McNeil
C J
CJ
Hunter
A J
AJ
Parsons
A A
AA
D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005609:Free Radicals / Q000378:metabolism; D007262:Infusions, Intravenous; D017078:Laser-Doppler Flowmetry / Q000379:methods; D008297:Male; D008881:Migraine Disorders / Q000188:drug therapy / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D005996:Nitroglycerin / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018170:Sumatriptan / Q000494:pharmacology* / Q000627:therapeutic use; D013481:Superoxides / Q000378:metabolism*
D005609:Free Radicals; D013481:Superoxides; D009569:Nitric Oxide; D018170:Sumatriptan; D005996:Nitroglycerin