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 micromol 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 micromol 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 gabapentin (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.
Neurosciences Research, SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, Harlow, Essex CM19 5AW.
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AA
Parsons
S
S
Bingham
P
P
Raval
S
S
Read
M
M
Thompson
N
N
Upton
D000758:Anesthesia; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D001578:Benzopyrans / Q000494:pharmacology*; D002415:Cats; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D006145:Guanethidine / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D007275:Injections, Intravenous; D012018:Reflex / Q000187:drug effects* / Q000502:physiology; D013565:Sympatholytics / Q000494:pharmacology; D013997:Time Factors; D012668:Trigeminal Ganglion / Q000502:physiology; D014276:Trigeminal Nerve / Q000502:physiology*; D014655:Vascular Resistance / Q000187:drug effects
D000927:Anticonvulsants; D001549:Benzamides; D001578:Benzopyrans; C102319:SB 204269; D013565:Sympatholytics; C118706:tonabersat; D006145:Guanethidine