Tonabersat (SB-220453) a novel benzopyran with anticonvulsant properties attenuates trigeminal nerve-induced neurovascular reflexes

1 The effects of tonabersat (SB-220453) were evaluated on trigeminal nerve ganglion stimulation-induced sensory-autonomic neurovascular reflexes in the anaesthetized cat. Comparisons were made to intravenous administration of carabersat (SB-204269), and to valproate, gabapentin and lamotrigine following intraduodenal administration. 2 There were no effects on resting blood pressure, heart rate, carotid blood flow or carotid vascular resistance for any compound evaluated. 3 Trigeminal nerve ganglion stimulation increased carotid blood flow by 65% and reduced vascular resistance by 41% with minimal effect on blood pressure (<10%) and no effect on heart rate. Intravenous infusion of tonabersat or carabersat (both 3.4 <mu>mol h(-1)) produced time related reductions in stimulation-induced responses with a maximal inhibition (relative to control) of 30 +/- 7% (n = 4), at 240 min for tonabersat and 33 +/- 4% (n = 3) at 180 min for carabersat. Tonabersat (11.5 mu mol h(-1)) produced a similar inhibitory effect (32 +/- 9%, n = 4) after 120 min of infusion. 4 Following intraduodenal administration of tonabersat, the maximal inhibition of nerve stimulation-induced responses was 55 +/- 4% at 120 min (n = 4) for tonabersat 10 mg kg(-1), and 24 +/- 2% after 180 min for 1 mg kg(-1) (n = 4). 5 Intraduodenal administration of sodium valproate (10 or 100 mg kg(-1) n = 4/group) had no effect on neurovascular reflexes. Maximal inhibition of nerve ganglion-stimulated reductions in carotid vascular resistance were observed at 150 min for lamotrigine (50 mg kg(-1), 52 +/- 12%, n = 4) and lgabapentin (100 mg kg(-1), 17 +/- 13%, n = 3). Lamotrigine 10 mg kg(-1) produced 22 +/- 11% (n = 3) inhibition after 180 min. 6 These data demonstrate blockade of trigeminal parasympathetic reflexes with tonabersat, carabersat and other anticonvulsants. These agents may therefore have therapeutic benefit in conditions where this type of reflex is evident.