The alkaloid 6-benzoylheteratisine inhibits voltage-gated Na super(+) channels in rat brain synaptosomes

• Published in: Neuropharmacology 1998-09, Vol.37 (9), p.1139-1146
• Main Authors: Gutser, U T, Gleitz, J
• Format: Article
• Language: English
• Subjects: 6-Benzoylheteratisine; Aconitum
• ISSN: 0028-3908

The effects of the Aconitum alkaloid 6-benzolheteratisine on the aconitine-, veratridine-, oubain- and KCI-induced alterations in free synaptosomal Na super(+) ([Na super(+)] sub(i)) and Ca super(2+) ([Ca2+] sub(i)) and the release of endogenous glutamate from rat cerebrocortical synaptosomes were investigated. [Na super(+)] sub(i) and [Ca super(2+)] sub(i) were fluorometrically determined employing SBFI and Fura-2 as the Na super(+) and Ca super(2+) sensitive dyes, respectively. Glutamate was detected by a continuous enzyme-linked fluorometric assay. The study revealed a concentration-dependent inhibitory effect of 6-benzoylheteratisine on aconitine-induced increases in [Na super(+)] sub(i), [Ca super(2+)] sub(i) and the release of glutamate. The IC sub(50) values were 4.1 mu M (Na super(+)), 4.8 mu M (Ca super(2+)) and 4.8 mu M (glutamate release). Application of 100 mu M 6-benzoylheteratisine after stimulation with 5 mu M veratridine also reduced the induced [Na super(+)] sub(i) and [Ca super(2+)] sub(i) with half-lives of 72.1 and 44.7 s, respectively. Furthermore, 100 mu M 6-benzoylheteratisine reduced the ouabain-induced Na super(+) influx to the same extent as the Na super(+) channel inhibitor tetrodotoxin, which points to an inhibition of non-activated Na super(+) channels by 6-benzoylheteratisine. Additionally, 100 mu M 6-benzoylheteratisine failed to affect the release of glutamate and the increase in [Ca super(2+)] sub(i) induced by 30 mM KCI, indicating that voltage-gated Ca super(2+) channels were not affected by 6-benzoylheteratisine. The data suggest an inhibitory effect of 6-benzoylheteratisine on voltage-gated Na super(+) channels as the only target, whereas mechanisms of Na super(+) and Ca super(2+) homoeostasis and pathways of glutamate release seem not to be affected by the drug.