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

Abstract

The effects of naratriptan, rizatriptan, and sumatriptan on arteriovenous oxygen saturation difference and carotid hemodynamics were compared in the anesthetized pig. 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 (n ϭ 19) or naratriptan, rizatriptan, or sumatriptan (0.63, 2.5, 10, 40, 160, 630, and 2,500 g/kg i.v.; n ϭ 7/group) were infused cumulatively. In naratriptan-, rizatriptan-, and sumatriptan-treated animals, jugular venous oxygen saturation decreased dose dependently (geometric mean ED 50 values of 3.1, 17.9, and 16.0 g/kg, respectively) concomitantly with increases in carotid vascular resistance. Rizatriptan significantly and dose dependently, from 160 g/kg, increased PvCO 2 (P Ͻ 0.05 versus vehicle). Naratriptan and sumatriptan also tended to increase PvCO 2 albeit nonstatistically significantly. All three triptans consistently evoked quantitatively similar carotid vasoconstriction, whereas decreases in jugular venous oxygen saturation (VOS) and increases in PvCO 2 had different magnitudes and occurred only in around one-half of the animals studied. Maximal variations in PvCO 2 were found to correlate highly with those in PvO 2 (P ϭ 0.002), but maximal variations in carotid resistance failed to correlate with those in PvCO 2 (P ϭ 0.76) or PvO 2 (P ϭ 0.28). The results demonstrate that the triptans investigated robustly produced carotid vasoconstriction, but elicited less consistent decreases in VOS and increases in jugular PvCO 2, possibly suggestive of distinct mechanisms. Collectively, the data suggest that triptan-induced increases in arteriovenous oxygen saturation difference and carbon dioxide partial pressure in venous blood draining the head are class effects.

Effects of 5-HT1B/1D Receptor Agonist Rizatriptan on Cerebral Blood Flow and Blood Volume in Normal Circulation

“…The CBF change was not caused by changes in systemic blood pressure nor blood gas because these parameters did not change after treatment. Although the systolic blood pressure was significantly increased after drug intake, which is caused by vasoconstriction of large vessels, the mean blood pressure did not change significantly as previously reported (Létienne et al, 2003). As flow-mediated vascular dilatation is inversely related to resting arterial diameter (Celermajer et al, 1992), cerebral arterioles would have driven the recovery of CBF even though larger vessels remained constricted.…”

Donitriptan Decreases Jugular Venous Oxygen Saturation in Rats in the Absence of Cranial Vasoconstriction: An Overlooked Mechanism of Antimigraine Action?

“…In group 5, rats (n ϭ 8) received an administration of sumatriptan (630 g/kg). The doses of donitriptan and sumatriptan used were chosen from previous studies in the anesthetized pig as those inducing maximal carotid vasoconstriction and maximal effects on oxygen saturation in jugular venous blood (Létienne et al, 2003a). In groups 6 and 7, rats were pretreated by an i.v.…”

“…Donitriptan, which has been evaluated for efficacy in the acute relief of migraine headache in phase II clinical trials (Dukat, 2001), and other triptans (Létienne et al, 2003a) augmented cerebral oxygen utilization and tissue metabolism. This additional mechanism of action may also be relevant to the acute headache-relieving effects of triptans as a whole.…”

Preclinical Neuropharmacology of Naratriptan

“…The vasoconstrictor effect of naratriptan as well as of some of the other triptans has, therefore, been generally assumed to be the result of 5-HT 1B -mediated effects (36,73,173). A direct cranial constrictor effect of naratriptan has been demonstrated in isolated vessels (22,137,175,194) and in some in vivo models (22,132).…”