Comparison of contractile responses to donitriptan and sumatriptan in the human middle meningeal and coronary arteries

Donitriptan is a potent, high efficacy agonist at 5-HT_1B/1D receptors. We investigated the contractile effects of donitriptan and sumatriptan on human isolated blood vessels of relevance to therapeutic efficacy in migraine (middle meningeal artery) and coronary adverse events (coronary artery). Furthermore, using the concentration-response curves in the middle meningeal artery, we predicted the plasma concentration needed for the therapeutic effect of donitriptan. Both donitriptan and sumatriptan contracted the middle meningeal artery with similar apparent efficacy (E_max: 103±8% and 110±12%, respectively), but the potency of donitriptan (pEC₅₀: 9.07±0.14) was significantly higher than that of sumatriptan (pEC₅₀: 7.41±0.08). In the coronary artery, the contraction to donitriptan was biphasic with a significantly higher maximal response (E_max: 29±6%) than sumatriptan (E_max: 14±2%; pEC₅₀: 5.71±0.16), yielding two distinct pEC₅₀ values (8.25±0.16 and 5.60±0.24). Incubation with the 5-HT₂ receptor antagonist ketanserin (10 μM) eliminated the low affinity component of the concentration-response curve of donitriptan and the resultant E_max and pEC₅₀ were 9±2% and 7.33±0.21, respectively. Ketanserin was without effect on the sumatriptan-induced contraction. Based on the middle meningeal artery contraction, concentrations (C_max) of donitriptan that may be expected to have a therapeutic efficacy equivalent to that of 50 and 100 mg sumatriptan are predicted to be around 2.5 and 4.3 nM, respectively. Such concentrations are likely to induce only a small coronary artery contraction of 2.9±1.5% and 3.8±2.0%, respectively; these are not different from those by C_max concentrations of sumatriptan (1.7±0.4% or 2.2±0.4%). The present results suggest that, like sumatriptan, donitriptan exhibits cranioselectivity and would be effective in aborting migraine attacks with a similar coronary side-effect profile as sumatriptan.