Donitriptan decreases jugular venous oxygen saturation in rats in the absence of cranial vasoconstriction: an overlooked mechanism of antimigraine action?
The aim of the present study was to determine whether donitriptan and sumatriptan decreased jugular venous oxygen saturation and increased carbon dioxide partial pressure in venous blood. However, previous studies conducted with these compounds cannot discriminate whether the decrease of venous oxygen saturation is dependent of cranial vasoconstrictor. In the present study, vehicle (n = 10), donitriptan (2.5, 10, and 40 microg/kg; n = 8) or sumatriptan (630 microg/kg; n = 8) were infused into the carotid artery in the anesthetized rat. Regional blood flows were evaluated in the presence of donitriptan (10 microg/kg; n = 6) or vehicle (n = 6). Jugular venous oxygen saturation was significantly decreased by donitriptan (from 10 microg/kg) with maximal changes of -32.9 +/- 8.0%. Jugular carbon dioxide partial pressure was increased by donitriptan, reaching maximal changes of 17.7 +/- 4.6% (P < 0.05 versus vehicle). Similarly, sumatriptan significantly decreased venous oxygen saturation and increased jugular carbon dioxide partial pressure. These changes induced by donitriptan are abolished by the 5-hydroxytryptamine (5-HT)(1B/1D) receptor antagonist GR 127935 (N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2-[-methyl-4(5-methyl-1,2,4)-oxadiazol-3-yl]-(1,1 biphenyl)-4-carboxamide dihydrochloride). In addition, donitriptan was devoid of significant effects on systemic arterial pressure, heart rate, or regional blood flows, including systemic arterial-jugular venous anastomotic, systemic, or cranial. The results demonstrate that donitriptan increases cerebral oxygen consumption by 5-HT(1B/1D) receptor activation in the absence of cranial vasoconstriction.
Létienne
Robert
R
Centre de Recherche Pierre Fabre, Castres, France. robert.letienne@pierre-fabre.com
Blanchet
Jean-Christophe
JC
Sole
Estelle
E
John
Gareth W
GW
Le Grand
Bruno
B
D000818:Animals; D001784:Blood Gas Analysis; D002560:Cerebrovascular Circulation / Q000502:physiology*; D006439:Hemodynamics / Q000187:drug effects; D007601:Jugular Veins / Q000378:metabolism; D008297:Male; D008881:Migraine Disorders / Q000188:drug therapy / Q000503:physiopathology*; D009570:Nitriles / Q000494:pharmacology* / Q000627:therapeutic use; D010069:Oxadiazoles / Q000494:pharmacology; D010100:Oxygen / Q000097:blood*; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D018170:Sumatriptan / Q000494:pharmacology; D014363:Tryptamines / Q000494:pharmacology* / Q000627:therapeutic use; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology
D009570:Nitriles; D010069:Oxadiazoles; D010879:Piperazines; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D014363:Tryptamines; C090701:GR 127935; C120143:donitriptan; D018170:Sumatriptan; D010100:Oxygen