Aconitum sp. alkaloids: the modulation of voltage-dependent Na+ channels, toxicity and antinociceptive properties.
Alkaloids from Aconitum sp., used as analgesics in traditional Chinese medicine, were investigated to elucidate their antinociceptive and toxic properties considering: (1) binding to Na+ channel epitope site 2, (2) alterations in synaptosomal Na+ and Ca2+ concentration ([Na+]i, [Ca2+]i), (3) arrhythmogenic action of isolated atria, (4) antinociceptive and (5) acute toxic action in mice. The study revealed a high affinity group (Ki 1 microM) and a low affinity group (Ki 10 microM) of alkaloids binding to site 2. The compounds of the high affinity group induce an increase in synaptosomal [Na+]i and [Ca2+]i (EC50 3 microM), are antinociceptive (ED50, 25 microg/kg), provoke tachyarrhythmia and are highly toxic (LD50 70 microg/kg), whereas low affinity alkaloids reduce [Ca2+]i, induce bradycardia and are less antinociceptive (ED50 20 mg/kg) and less toxic (LD50 30 mg/kg). These results suggest that the alkaloids can be grouped in Na+ channel activating and blocking compounds, but none of the alkaloids seem to be suitable as analgesics because of the low LD50/ED50 values.
Friese
J
J
Institute of Naturheilkunde, University Clinics Ulm, Germany. jutta.friese@medizin.uni-ulm.de
Gleitz
J
J
Gutser
U T
UT
Heubach
J F
JF
Matthiesen
T
T
Wilffert
B
B
Selve
N
N
D000157:Aconitine / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D000470:Alkaloids / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced; D002118:Calcium / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D004365:Drugs, Chinese Herbal / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D015640:Ion Channel Gating; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D010147:Pain Measurement; D051381:Rats; D017208:Rats, Wistar; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000187:drug effects* / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D000470:Alkaloids; D004365:Drugs, Chinese Herbal; D015222:Sodium Channels; D012964:Sodium; D002118:Calcium; D000157:Aconitine