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

Abstract

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.