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 pentobarbitoneanesthetized 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 ϭ 9) or donitriptan (0.01, 0.04, 0.16, 0.63, 2.5, 10, and 40 g/kg, n ϭ 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 [ED 50 0.5 (0.3-1.1) g/kg], in parallel with increases in carotid vascular resistance [ED 50 0.9 (0.7-1.1) g/kg]. Since arterial oxygen saturation and partial pressure remained unchanged, donitriptan significantly increased arteriovenous oxygen saturation difference from 0.63 g/kg (maximal variation: 57 Ϯ 18%, P Ͻ 0.05 compared with vehicle). Unexpectedly, donitriptan from 2.5 g/kg induced marked and significant increases in carbon dioxide partial pressure (pVCO 2 ) in venous blood (maximal increase 18.8 Ϯ 5.7%; P Ͻ 0.05 compared with vehicle). Pretreatment with GR 127935 (0.63 mg/kg, n ϭ 5) abolished the fall in venous oxygen saturation and the increase in carotid vascular resistance and reduced the increases in pVCO 2 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 pVCO 2 , an effect upon cerebral oxygen consumption and metabolism is suggested in addition to cranial vasoconstriction, which may be relevant to its headache-relieving effects.Donitriptan is a unique high-efficacy agonist at 5-HT 1B/1D receptors; it is currently being evaluated for efficacy in the acute relief of migraine headache in phase II clinical trials (Dukat, 2001;John et al., 1999John et al., , 2000. One of the key pharmacological actions of donitriptan is 5-HT 1B receptor-medi- Tom et al., 2002). Before the advent of the triptans, the nonselective 5-HT 1B receptor agonist ergotamine (Villalón et al., 1999) was also shown to elicit selective carotid vasoconstriction confined to cephalic AVAs (Johnston and Saxena, 1978). Moreover, increases in AVOSD due to decreases in jugular venous oxygen saturation and oxygen partial pressure (pO 2 ) without affecting systemic arterial oxygen saturation or pO 2 were also observed in this study (Johnston and Saxena, 1978). However, it is presently unknown whether the recently described triptan 5-HT 1B/1D receptor agonistinduced increases in AVOSD are due to changes in systemic arterial or jugular venous oxygen saturation, or both.The aim of the present investigation was therefore to eluArticle, publication date, and citation information can be found at http://jpet.aspetjournals.org. DOI: 10.1124/jpet.102...

Investigation of the Effects of Naratriptan, Rizatriptan, and Sumatriptan on Jugular Venous Oxygen Saturation in Anesthetized Pigs: Implications for Their Mechanism of Acute Antimigraine Action

“…These effects explain the observed increases in arteriovenous oxygen saturation difference with donitriptan, and are associated with closure of cephalic arteriovenous anastomoses (AVAs; Tom et al, 2002). However, the donitriptan-induced decreases in jugular venous oxygen saturation were unexpectedly accompanied by increases in jugular venous carbon dioxide partial pressure (Létienne et al, 2003), suggesting that in addition to closure of cephalic AVAs, donitriptan increases cerebral oxygen extraction and tissue metabolism (Létienne et al, 2003).…”

“…We recently reported experiments in anesthetized pigs in which donitriptan (John et al, 1999(John et al, , 2000Dukat, 2001), via 5-HT 1B receptor activation, decreased the hemoglobin oxygen saturation of venous blood draining the head concomitantly with cranial vasoconstriction (Létienne et al, 2003). These effects explain the observed increases in arteriovenous oxygen saturation difference with donitriptan, and are associated with closure of cephalic arteriovenous anastomoses (AVAs; Tom et al, 2002).…”

“…The objective of the present study was to determine whether the representative triptans naratriptan, rizatriptan, and sumatriptan could decrease jugular venous oxygen saturation and increase jugular carbon dioxide partial pressure as previously described for donitriptan (Létienne et al, 2003) in the anesthetized pig. The three triptans investigated dose dependently decreased jugular venous hemoglobin oxygen saturation without affecting systemic arterial oxygen saturation, leading to increases in cephalic AVOSD.…”

“…The arterial and venous oxygen saturation and the arteriovenous oxygen saturation difference (AVOSD) were calculated as described previously (Létienne et al, 2003).…”

“…The observation that donitriptan promotes cerebral oxygen utilization and tissue metabolism (Létienne et al, 2003) implies that this additional mechanism of action may be relevant to the acute headache-relieving effects of donitriptan, and possibly other triptans.…”