Vol. 305, Issue 2, 749-754, May 2003

Donitriptan Selectively Decreases Jugular Venous Oxygen Saturation in the Anesthetized Pig: Further Insights into Its Mechanism of Action Relevant to Headache Relief

Robert Létienne, Yvan Verscheure, Michel Perez, Bruno Le Grand, Francis C. Colpaert and Gareth W. John

Centre de Recherche Pierre Fabre, Castres Cedex, France

The effects of donitriptan on systemic arterial-jugular venous oxygen saturation difference were evaluated in pentobarbitone-anesthetized pigs. Oxygen and carbon dioxide partial pressures in systemic arterial and jugular venous blood as well as hemoglobin oxygen saturation were determined by conventional blood gas analysis. Vehicle (40% polyethyleneglycol in saline, n = 9) or donitriptan (0.01, 0.04, 0.16, 0.63, 2.5, 10, and 40 µg/kg, n = 7) were cumulatively infused over 15 min/dose. The involvement of 5-hydroxytryptamine_1B (5-HT_1B) receptors was assessed in the presence of the 5-HT_1B/1D receptor antagonist, GR 127935. Donitriptan decreased markedly and dose dependently jugular venous oxygen saturation [ED₅₀ 0.5 (0.3-1.1) µg/kg], in parallel with increases in carotid vascular resistance [ED₅₀ 0.9 (0.7-1.1) µg/kg]. Since arterial oxygen saturation and partial pressure remained unchanged, donitriptan significantly increased arteriovenous oxygen saturation difference from 0.63 µg/kg (maximal variation: 57 ± 18%, P < 0.05 compared with vehicle). Unexpectedly, donitriptan from 2.5 µg/kg induced marked and significant increases in carbon dioxide partial pressure (pVCO₂) in venous blood (maximal increase 18.8 ± 5.7%; P < 0.05 compared with vehicle). Pretreatment with GR 127935 (0.63 mg/kg, n = 5) abolished the fall in venous oxygen saturation and the increase in carotid vascular resistance and reduced the increases in pVCO₂ induced by donitriptan. The results demonstrate that donitriptan, via 5-HT_1B receptor activation, decreases the oxygen saturation of venous blood draining the head, concomitantly with cranial vasoconstriction. Since donitriptan also increased pVCO₂, an effect upon cerebral oxygen consumption and metabolism is suggested in addition to cranial vasoconstriction, which may be relevant to its headache-relieving effects.